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Sample records for allograft rejection model1

  1. Renal allograft rejection: sonography and scintigraphy

    SciTech Connect

    Singh, A.; Cohen, W.N.

    1980-07-01

    A total of 30 renal allograft patients who had sonographic B scanning and radionuclide studies of the transplant was studied as to whether: (1) the allograft rejection was associated with any consistent and reliable sonographic features and (2) the sonograms complemented the radionuclide studies. Focal areas of decreased parenchymal echogenicity were the most striking and consistent sonographic finding in chymal echogenicity were the most striking and consistens sonographic finding in allograft rejection. This was observed in most of the patients exhibiting moderate or severe rejection, but was frequently absent with mild rejection. Areas of decreased parenchymal echogenicity were not seen during episodes of acute tubular necrosis. Therefore, sonography showing zones of decreased parenchymal echogenicity was complementary to radionuclide studies in the diagnosis of allograft rejection versus acute tubular necrosis. Corticomedullary demarcation was difficult to interpret because of technical variables, and was inconsistently related to rejection in this series.

  2. Mechanisms of allograft rejection of corneal endothelium

    SciTech Connect

    Tagawa, Y.; Silverstein, A.M.; Prendergast, R.A.

    1982-07-01

    The local intraocular graft-vs.-host (GVH) reaction, involving the destruction of the corneal endothelial cells of the rabbit host by sensitized donor lymphoid cells, has been used to study the mechanism of corneal allograft rejection. Pretreatment of donor cells with a specific mouse monoclonal hybridoma anti-T cell antibody and complement suppresses the destructive reaction, suggesting that a cellular-immune mechanism is primarily involved. Pretreatment of donor cells with mitomycin-C completely abolishes the local GVH reaction, indicating that the effector lymphocytes must undergo mitosis within the eye before they can engage in target cell destruction. Finally, studies of the local GVH reaction in irradiated leukopenic recipients or in preinflamed rabbit eyes suggest that host leukocytes may contribute nonspecifically to enhance the destructive process. These studies show that the local ocular GVH reaction may provide a useful model for the study of the mechanisms involved in the rejection of corneal allografts.

  3. Allograft rejection in cattle with bovine leukocyte adhesion deficiency.

    PubMed

    Müller, K E; Rutten, V P; Becker, C K; Hoek, A; Bernadina, W E; Wentink, G H; Figdor, C G

    1995-09-01

    In the present investigation cell-mediated immunity in animals with bovine leukocyte adhesion deficiency (BLAD) was studied by means of skin transplantation experiments. Autograft and allograft behaviour in animals with BLAD was compared with the behaviour of simultaneously transplanted autografts and allografts in healthy controls. Allograft survival time was prolonged in three BLAD cattle (28, 30, and 72 days) compared to six healthy controls (12-14 days). When transplantations were repeated on one animal with BLAD using skin grafts from the same donor, accelerated rejection was observed (allograft survival time decreased from 72 days at primary to 35 days at secondary and to 21 days at tertiary transplantation), suggesting the development of immunological memory. Graft-infiltrating lymphocytes that were obtained from allograft biopsies during the period of rejection, were shown to be from recipient origin (beta 2-integrin negative). Our findings demonstrate that, although prolonged allograft survival is observed in cattle with BLAD, skin allografts are ultimately rejected. PMID:8533316

  4. Autophagy in allografts rejection: A new direction?

    PubMed

    Sun, Hukui; Cheng, Dayan; Ma, Yuanyuan; Wang, Huaiquan; Liang, Ting; Hou, Guihua

    2016-03-18

    Despite the introduction of new and effective immunosuppressive drugs, acute cellular graft rejection is still a major risk for graft survival. Modulating the dosage of immunosuppressive drugs is not a good choice for all patients, new rejection mechanisms discovery are crucial to limit the inflammatory process and preserve the function of the transplant. Autophagy, a fundamental cellular process, can be detected in all subsets of lymphocytes and freshly isolated naive T lymphocytes. It is required for the homeostasis and function of T lymphocytes, which lead to cell survival or cell death depending on the context. T cell receptor (TCR) stimulation and costimulator signals induce strong autophagy, and autophagy deficient T cells leads to rampant apoptosis upon TCR stimulation. Autophagy has been proved to be activated during ischemia-reperfusion (I/R) injury and associated with grafts dysfunction. Furthermore, Autophagy has also emerged as a key mechanism in orchestrating innate and adaptive immune response to self-antigens, which relates with negative selection and Foxp3(+) Treg induction. Although, the role of autophagy in allograft rejection is unknown, current data suggest that autophagy indeed sweeps across both in the graft organs and recipients lymphocytes after transplantation. This review presents the rationale for the hypothesis that targeting the autophagy pathway could be beneficial in promoting graft survival after transplantation. PMID:26876576

  5. Total lymphoid irradiation for treatment of intractable cardiac allograft rejection

    SciTech Connect

    Hunt, S.A.; Strober, S.; Hoppe, R.T.; Stinson, E.B. )

    1991-03-01

    The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for 'salvage' therapy of cardiac allograft rejection unresponsive to conventional therapy.

  6. Monitoring of corneal allograft rejection using laser flare meter

    NASA Astrophysics Data System (ADS)

    Zarnowski, Tomasz; Haszcz, Dariusz; Rakowska, Ewa; Zagorski, Zbigniew

    1998-10-01

    The purpose of this study was to quantify noninvasively, with the use of laser-flare meter the alterations of the blood-aqueous barrier following penetrating keratoplasty. This could diagnose objectively disruption of this barrier in eyes with early allograft rejection, possible even before manifestation of the clinical signs and would help to monitor the efficacy of the treatment. We used the laser flare-meter (Kowa FM-500) to investigate alteration of the blood-aqueous barrier following uncomplicated penetrating keratoplasty (PK) and in corneal allograft rejection. Examination was performed in 50 eyes of 48 patients after uncomplicated PK (7 days to 12 months after PK), in 20 normal control eyes and in 8 patients with acute allograft rejection. Flare values after uncomplicated keratoplasty slowly decreased in time reaching nearly control values 6 - 12 months postoperatively. They were considerably higher for acute allograft rejection compared to eyes following uncomplicated PK and normal control group. Actually, they tended to diminish gradually after systemic and topical administration of steroids and/or immunosuppressants. Application of laser tyndalometry has been proven to be highly useful in the follow up of patients after perforating keratoplasty-especially high risk grafts, it helps to detect objectively early allograft rejection and is beneficial in monitoring the effectiveness of the treatment.

  7. Imaging-based diagnosis of acute renal allograft rejection

    PubMed Central

    Thölking, Gerold; Schuette-Nuetgen, Katharina; Kentrup, Dominik; Pawelski, Helga; Reuter, Stefan

    2016-01-01

    Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the “gold-standard”. However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasound-based methods. PMID:27011915

  8. Imaging mouse lung allograft rejection with 1H MRI

    PubMed Central

    Guo, Jinbang; Huang, Howard J.; Wang, Xingan; Wang, Wei; Ellison, Henry; Thomen, Robert P.; Gelman, Andrew E.; Woods, Jason C.

    2014-01-01

    Purpose To demonstrate that longitudinal, non-invasive monitoring via MRI can characterize acute cellular rejection (ACR) in mouse orthotopic lung allografts. Methods Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig vs anti-CD4/anti-CD8 treated groups. A two-dimensional multi-slice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at post-operative days 3, 7 and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. Results Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 post transplantation (0.046→0.789, P < 0.05), despite large inter-mouse variations; this was consistent with histopathologic evidence of rejection. Compliance of the control-Ig allograft decreased significantly over time (0.013→0.003, P < 0.05), but remained constant in mice treated with anti-CD4/anti-CD8 antibodies. Conclusion Lung allograft rejection in individual mice can be monitored by lung parenchymal signal changes and by lung compliance through MRI. Longitudinal imaging can help us better understand the time course of individual lung allograft rejection and response to treatment. PMID:24954886

  9. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection.

    PubMed

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E; Padera, Robert F; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D'Agostino, Emmanuel; Goldberg, Hilary J; Perrella, Mark A; Forteza, Rosanna Malbran; Rosas, Ivan O; Visner, Gary; El-Chemaly, Souheil

    2015-11-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  10. Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

    PubMed Central

    Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

    2015-01-01

    Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

  11. Corneal Allograft Rejection: Immunopathogenesis to Therapeutics

    PubMed Central

    Qazi, Yureeda; Hamrah, Pedram

    2014-01-01

    Corneal transplantation is among the most successful solid organ transplants. However, despite low rejection rates of grafts in the ‘low-risk’ setting, rejection can be as high as 70% when grafted into ‘high-risk’ recipient beds. Under normal homeostatic conditions, the avascular cornea provides a unique environment that facilitates immune and angiogenic privilege. An imbalance in pro-inflammatory, angiogenic and lymphangiogenic mediators leads to a breakdown in corneal immune privilege with a consequent host response against the donor graft. Recent developments in lamellar and endothelial keratoplasties have reduced the rates of graft rejection even more, while providing improved visual outcomes. The corneal layer against which an immune response is initiated, largely determines reversibility of the acute episode. While epithelial and stromal graft rejection may be treated with topical corticosteroids with higher success, acute endothelial rejection mandates a more aggressive approach to therapy due to the lack of regenerative capacity of this layer. However, current immunosuppressive regimens come with the caveat of ocular and systemic side effects, making prolonged aggressive treatment undesirable. With the advent of biologics, efficacious therapies with a superior side effect profile are on the horizon. In our review we discuss the mediators of ocular immune privilege, the roles of cellular and molecular immune players in graft rejection, with a focus on human leukocyte antigen and antigen presenting cells. Furthermore, we discuss the clinical risk factors for graft rejection and compare rates of rejection in lamellar and endothelial keratoplasties to traditional penetrating keratoplasty. Lastly, we present the current and upcoming measures of therapeutic strategies to manage and treat graft rejection, including an overview of biologics and small molecule therapy. PMID:24634796

  12. Graft vasculopathy in the skin of a human hand allograft: implications for diagnosis of rejection of vascularized composite allografts.

    PubMed

    Kanitakis, Jean; Karayannopoulou, Georgia; Lanzetta, Marco; Petruzzo, Palmina

    2014-11-01

    Whereas vascularized composite allografts often undergo acute rejections early in the postgraft period, rejection manifesting with severe vascular changes (graft vasculopathy) has only been observed on three occasions in humans. We report a hand-allografted patient who developed severe rejection following discontinuation of the immunosuppressive treatment. It manifested clinically with erythematous maculopapules on the skin and pathologically with graft vasculopathy that affected both large vessels and smaller cutaneous ones. The observation that graft vasculopathy can affect skin vessels shows that it is amenable to diagnosis with usual skin biopsy as recommended for the follow-up of these allografts. Graft vasculopathy developing in the setting of vascularized composite allografts likely represents chronic rejection due to under-immunosuppression and, if confirmed, should be included in a future update of the Banff classification of vascularized composite allograft rejection. PMID:25041139

  13. The composition of the microbiota modulates allograft rejection.

    PubMed

    Lei, Yuk Man; Chen, Luqiu; Wang, Ying; Stefka, Andrew T; Molinero, Luciana L; Theriault, Betty; Aquino-Michaels, Keston; Sivan, Ayelet S; Nagler, Cathryn R; Gajewski, Thomas F; Chong, Anita S; Bartman, Caroline; Alegre, Maria-Luisa

    2016-07-01

    Transplantation is the only cure for end-stage organ failure, but without immunosuppression, T cells rapidly reject allografts. While genetic disparities between donor and recipient are major determinants of the kinetics of transplant rejection, little is known about the contribution of environmental factors. Because colonized organs have worse transplant outcome than sterile organs, we tested the influence of host and donor microbiota on skin transplant rejection. Compared with untreated conventional mice, pretreatment of donors and recipients with broad-spectrum antibiotics (Abx) or use of germ-free (GF) donors and recipients resulted in prolonged survival of minor antigen-mismatched skin grafts. Increased graft survival correlated with reduced type I IFN signaling in antigen-presenting cells (APCs) and decreased priming of alloreactive T cells. Colonization of GF mice with fecal material from untreated conventional mice, but not from Abx-pretreated mice, enhanced the ability of APCs to prime alloreactive T cells and accelerated graft rejection, suggesting that alloimmunity is modulated by the composition of microbiota rather than the quantity of bacteria. Abx pretreatment of conventional mice also delayed rejection of major antigen-mismatched skin and MHC class II-mismatched cardiac allografts. This study demonstrates that Abx pretreatment prolongs graft survival, suggesting that targeting microbial constituents is a potential therapeutic strategy for enhancing graft acceptance. PMID:27322054

  14. Injury-induced allograft rejection: A rendezvous with evolution.

    PubMed

    Land, Walter G

    2013-01-01

    Modern immunology, in many ways, is based on three major paradigms: the clonal selection theory, the pattern recognition theory, and the danger/injury theory. The last theory holds that any cell stress and tissue injury, including allograft injury, via induction of damage-associated molecular patterns, induces immunity, including alloimmunity, leading to allograft rejection. On the other hand, the concept precludes that non-self per se induces immunity as proposed by the two former theories. Recently, the danger/injury model has gained considerable acceptance by immunologists, in particular as promoted by new insights into the function of the mammalian gut microbiota, representing a huge assemblage of non-self. Harboring microbiota by hosts is characterized by the fact that harmless noninjurious commensal microbes are protected by innate immunity-based tolerance, whereas intestinal injury-causing pathogenic microbes are immunologically attacked. Plausibility and validity of the danger/injury concept is stringently supported by observations of similar phenomena across the tree of life: the ability of the immune system to discriminate between harmful life-threatening non-self to induce immunity and harmless beneficial non-self to induce tolerance has apparently emerged during evolution. Immune defense responses to injuring/injured non-self (e.g., as reflected by plant resistance to biotic and abiotic stresses on one hand, and allograft rejection on the other hand) as well as immunity-controlled protection of beneficial non-self (e.g., as reflected by microbiota and the fetus of placental mammals) are processes in the interest of evolution and, thus, evolved under pressure across the phylogenetic tree. PMID:25095509

  15. A retrospective clinical study of Xinjiang Uygur patients with corneal allograft rejection

    PubMed Central

    Maimaitiming, Reziwan; Yang, Xin; Wupuer, Kelala; Ye, Nan; Kong, Na; Gu, Baoyu; Fan, Yuanyuan; Shao, Lan; Pan, Zhiqiang

    2015-01-01

    Background: To explore the causes of corneal allograft rejection in Xinjiang Uygur patients and the factors that affect rejection through a retrospective clinical analysis. Methods: A retrospective analysis of 126 Uygur cases from January 2010 to November 2014 in which corneal transplantation had been performed at the Xinjiang Urumqi ENT hospital. Of the treated patients, 85 eyes belonged to male patients and 41 eyes belonged to female patients. Patients were aged 10-77 years (mean age 46.14 ± 8.20 years). Surgical methods included penetrating keratoplasty (75 eyes) and lamellar keratoplasty (38 eyes). Follow-up time ranged from 0.5 to 3 years and a total of seven pre-operative keratopathies were observed: walleye, corneal ulcer, bullous keratopathy, corneal degeneration. Eye changes included 72 cases of limbal vascularization and 15 cases of high intraocular pressure. Allograft rejection was observed in 25 eyes. Results: The pre-operative keratopathies associated with the highest incidences of allograft rejection were: viral corneal ulcer, bullous keratopathy, adhesive walleye, and fungal corneal ulcers. The rate of allograft rejection using avascular corneal tissue was 10%, while the rate was 36% with severly-vascularized cornea. The earliest time of rejection was 20 days after surgery, while the latest was 16.4 months after surgery. Heavy corneal vascularization is associated with more rapid post-operative rejection. The rate of allograft rejection was higher after combined surgery when compared to penetrating keratoplasty or lamellar keratoplasty alone, while the rate was higher with penetrating keratoplasty than with lamellar keratoplasty. With increasing graft diameter, there was an increase in post-operative allograft rejection. Allograft rejection was significantly increased when graft diameter was above 7.75 mm. Conclusion: The major cause of corneal allograft rejection is viral corneal ulcers. High corneal vascularization, combined surgical methods

  16. B-Cell-Mediated Strategies to Fight Chronic Allograft Rejection

    PubMed Central

    Dalloul, Ali

    2013-01-01

    Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after 1 year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of “tolerant” vs. effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic allograft

  17. Local allograft irradiation as an adjunct for treating severe resistant rejection after liver transplantation in adults.

    PubMed

    Ramanathan, Rajesh; Sharma, Amit; Kaspar, Matthew; Behnke, Martha; Song, Shiyu; Stravitz, R Todd; Cotterell, Adrian; Posner, Marc; Fisher, Robert A

    2015-01-01

    Acute rejection after liver transplantation occurs in one-third of all recipients and can be managed with conventional rejection therapy in the majority of cases. In rare instances, patients with severe acute rejection may be refractory to or have contraindications for conventional therapies. This case series evaluates the role of local allograft irradiation (LAI) as an adjunct for patients with rejection that is refractory to or contraindicated for conventional therapies. Additionally, the literature on the use of radiation therapy for reversing rejection in solid organ transplantation is reviewed. Five patients underwent 9 LAI treatments: 2 had refractory rejection, and 1 each had a malignancy, a concurrent life-threatening infection, and serum sickness with antibody therapy. Conventional rejection therapies included steroids, calcineurin inhibitors, and antithymocyte globulin. LAI consisted of 3 cycles of 1.5 Gy directed toward the liver allograft. Two of the 5 patients remained alive with excellent graft function. Six of the 9 treatments were successful in rescuing the liver allograft (reversing the rejection episode). Treatment success was associated with lower pretreatment serum bilirubin levels and higher pretreatment alanine aminotransferase levels. Compared with patients with immunosuppression-responsive severe acute rejection, those requiring LAI trended toward a later onset of first rejection. In conclusion, local irradiation of liver allografts can be a useful adjunct in patients for whom conventional options have been exhausted or cannot be used. The ability of LAI to reverse allograft dysfunction and promote patient survival appears to be greatest before the onset of severe cholestatic injury. PMID:25287272

  18. Alternatively expressed genes identified in the CD4+ T cells of allograft rejection mice.

    PubMed

    Xu, Jia; Wang, Dan; Zhang, Chao; Song, Jing; Liang, Ting; Jin, Weirong; Kim, Yeong C; Wang, San Ming; Hou, Guihua

    2011-01-01

    Allograft rejection is a leading cause for the failure of allotransplantation. CD4(+) T cells play critical roles in this process. The identification of genes that alternatively expressed in CD4(+) T cells during allograft rejection will provide critical information for studying the mechanism of allograft rejection, finding specific gene markers for monitoring, predicting allograft rejection, and opening new ways to regulate and prevent allograft rejection. Here, we established allograft and isograft transplantation models by adoptively transferring wild-type BALB/c mouse CD4(+) T cells into severe combined immunodeficient (SCID) mice with a C57BL/6 or BALB/c mouse skin graft. Using the whole transcriptome sequencing-based serial analysis of gene expression (SAGE) technology, we identified 97 increasingly and 88 decreasingly expressed genes that may play important roles in allograft rejection and tolerance. Functional classification of these genes shows that apoptosis, transcription regulation, cell growth and maintenance, and signal transduction are among the frequently changed functional groups. This study provides a genome-wide view for the candidate genes of CD4(+) T cells related to allotransplantation, and this report is a good resource for further microarray studies and for identifying the specific markers that are associated with clinical organ transplantations. PMID:21294963

  19. Acute allograft rejection and immunosuppression: influence on endogenous melatonin secretion.

    PubMed

    Cardell, Markus; Jung, Florian Johannes; Zhai, Wei; Hillinger, Sven; Welp, Andre; Manz, Bernhard; Weder, Walter; Korom, Stephan

    2008-04-01

    Melatonin displays a dose-dependent immunoregulatory effect in vitro and in vivo. Exogenous high-dose melatonin therapy exerted an immunosuppressive effect, abrogating acute rejection (AR), significantly prolonging transplant survival. Endogenous melatonin secretion, in response to heterotopic rat cardiac allograft transplantation (Tx), was investigated during the AR response and under standardized immunosuppressive maintenance therapy with cyclosporin A (CsA) and rapamycin (RPM). Recipients of syngeneic transplants, and recipients of allogeneic grafts, either untreated or receiving immunosuppressive therapy constituted the experimental groups. Endogenous circadian melatonin levels were measured at 07:00, 19:00, and 24:00 hr, using a novel radioimmunoassay (RIA) procedure, under standardized 12-hr-light/dark-conditions (light off: 19:00 hr; light on: 07:00 hr), before and after Tx. Neither the operative trauma, nor the challenge with a perfused allograft or the AR response influenced endogenous melatonin peak secretion. Immunosuppressive therapy with CsA led to a significant increase in peak secretion, measured for days 7 (212 +/- 40.7 pg/mL; P < 0.05), 14 (255 +/- 13.9 pg/mL; P < 0.001), and 21 (219 +/- 34 pg/mL; P < 0.01) after Tx, as compared with naïve animals (155 +/- 25.8 pg/mL). In contrast, treatment with RPM significantly decreased the melatonin peak post-Tx up to day 7 (87 +/- 25.2 pg/mL; P < 0.001), compared with naïve animals (155 +/- 25.8 pg/mL). These findings imply a robust nature of the endogenous circadian melatonin secretion kinetics, even against the background of profound allogeneic stimuli. Immunosuppressive maintenance therapy with CsA and RPM modulated early melatonin secretion, indicating a specific secondary action of these drugs. Further studies are necessary to disclose the long-term effect of immunosuppressive therapy on circadian melatonin secretion in transplant recipients. PMID:18339121

  20. Equivalence of topical clobetasone and dexamethasone in experimental corneal allograft rejection.

    PubMed Central

    Wilhelmus, K R; Hunter, P A; Rice, N S

    1981-01-01

    We produced experimental immune reactions by exchanging peripheral corneal transplants between rabbits. Clobetasone butyrate 0.1% and dexamethasone phosphate 0.1% eye drops were equally effective in delaying corneal allograft rejection. Images PMID:7032579

  1. Interplay between Immune responses to HLA and Non-HLA self-antigens in allograft rejection

    PubMed Central

    Angaswamy, Nataraju; Tiriveedhi, Venkataswarup; Sarma, Nayan J; Subramanian, Vijay; Klein, Christina; Wellen, Jason; Shenoy, Surendra; Chapman, William C; Mohanakumar, T.

    2013-01-01

    Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction. PMID:23876679

  2. Imaging of cardiac allograft rejection in dogs using indium-111 monoclonal antimyosin Fab

    SciTech Connect

    Addonizio, L.J.; Michler, R.E.; Marboe, C.; Esser, P.E.; Johnson, L.L.; Seldin, D.W.; Gersony, W.M.; Alderson, P.O.; Rose, E.A.; Cannon, P.J.

    1987-03-01

    The acute rejection of cardiac allografts is currently diagnosed by the presence of myocyte necrosis on endomyocardial biopsy. We evaluated the efficacy of noninvasive scintigraphic imaging with indium-111-labeled anticardiac myosin Fab fragments (indium-111 antimyosin) to detect and quantify cardiac allograft rejection. Six dogs that had intrathoracic heterotopic cardiac allograft transplantation were injected with indium-111 antimyosin and planar and single photon emission computed tomographic (SPECT) images were obtained in various stages of acute and subacute rejection. Four dogs had an allograft older than 8 months and had been on long-term immunosuppressive therapy; two dogs had an allograft less than 2 weeks old and were not on immunosuppressive therapy. Count ratios comparing heterotopic with native hearts were calculated from both SPECT images and in vitro scans of excised and sectioned hearts and were compared with the degree of rejection scored by an independent histopathologic review. Indium-111 antimyosin uptake was not visible in planar or SPECT images of native hearts. Faint diffuse uptake was apparent in cardiac allografts during long-term immunosuppression and intense radioactivity was present in hearts with electrocardiographic evidence of rejection. The heterotopic to native heart count ratios in SPECT images correlated significantly with the count ratios in the excised hearts (r = 0.93) and with the histopathologic rejection score (r = 0.97). The distribution of indium-111 antimyosin activity in right and left ventricles corresponded to areas of histopathologic abnormalities.

  3. SPECT- and PET-Based Approaches for Noninvasive Diagnosis of Acute Renal Allograft Rejection

    PubMed Central

    Pawelski, Helga; Schnöckel, Uta; Kentrup, Dominik; Grabner, Alexander; Schäfers, Michael; Reuter, Stefan

    2014-01-01

    Molecular imaging techniques such as single photon emission computed tomography (SPECT) or positron emission tomography are promising tools for noninvasive diagnosis of acute allograft rejection (AR). Given the importance of renal transplantation and the limitation of available donors, detailed analysis of factors that affect transplant survival is important. Episodes of acute allograft rejection are a negative prognostic factor for long-term graft survival. Invasive core needle biopsies are still the “goldstandard” in rejection diagnostics. Nevertheless, they are cumbersome to the patient and carry the risk of significant graft injury. Notably, they cannot be performed on patients taking anticoagulant drugs. Therefore, a noninvasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review SPECT- and PET-based approaches for noninvasive molecular imaging-based diagnostics of acute transplant rejection. PMID:24804257

  4. Cutting edge: membrane lymphotoxin regulates CD8(+) T cell-mediated intestinal allograft rejection.

    PubMed

    Guo, Z; Wang, J; Meng, L; Wu, Q; Kim, O; Hart, J; He, G; Zhou, P; Thistlethwaite, J R; Alegre, M L; Fu, Y X; Newell, K A

    2001-11-01

    Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4(+) T cells are necessary for rejection. When CD8(+) T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8(+) T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8(+) T cells. This effect was associated with decreased monokine induced by IFN-gamma (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4(+) T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8(+) T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection. PMID:11673481

  5. Sensitivity of scintigraphy with /sup 111/In-lymphocytes for detection of cardiac allograft rejection

    SciTech Connect

    Eisenberg, S.B.; Eisen, H.J.; Sobel, B.E.; Bergmann, S.R.; Bolman, R.M. 3d.

    1988-12-01

    We recently demonstrated the feasibility of noninvasive detection of cardiac allograft rejection after administration of indium-111-labeled lymphocytes. To determine the sensitivity and specificity of the technique, as well as its value for delineating the severity of rejection, we studied 16 dogs with heterotopic thoracic cardiac allografts. Five animals were evaluated while exposed to immunosuppressive agents. Animals were scanned sequentially after administration of 100-400 microCi of indium-111-labeled autologous lymphocytes. Myocardial lymphocyte infiltration was expressed as the indium excess (IE), defined as the ratio of indium activity of the transplant or native heart compared with that in blood. Scintigraphic results were compared with characteristics of simultaneously obtained endomyocardial biopsies. Among 17 biopsy documented episodes of rejection, 16 were detected scintigraphically. Among 18 biopsies with no evidence of rejection, scintigraphy was uniformly negative. Thus, the sensitivity and specificity of scintigraphy were 94 and 100%, respectively. Biopsies graded as showing no rejection were associated with an IE of 0.3 +/- 0.5 (+/- SD); those graded as mild, 2.8 +/- 1.7; those as moderate, 10.7 +/- 7.2; and those graded as indicative of severe rejection, 14.2 +/- 4.5. Thus, scintigraphy with indium-111-labeled lymphocytes sensitively and specifically detects cardiac allograft rejection and delineates the intensity of the rejection process. It should be useful clinically for assessing potential allograft rejection noninvasively.

  6. Detection and measurement of tubulitis in renal allograft rejection

    NASA Astrophysics Data System (ADS)

    Hiller, John B.; Chen, Qi; Jin, Jesse S.; Wang, Yung; Yong, James L. C.

    1997-04-01

    Tubulitis is one of the most reliable signs of acute renal allograft rejection. It occurs when mononuclear cells are localized between the lining tubular epithelial cells with or without disruption of the tubular basement membrane. It has been found that tubulitis takes place predominantly in the regions of the distal convoluted tubules and the cortical collecting system. The image processing tasks are to find the tubule boundaries and to find the relative location of the lymphocytes and epithelial cells and tubule boundaries. The requirement for accuracy applies to determining the relative locations of the lymphocytes and the tubule boundaries. This paper will show how the different sizes and grey values of the lymphocytes and epithelial cells simplify their identification and location. Difficulties in finding the tubule boundaries image processing will be illustrated. It will be shown how proximate location of epithelial cells and the tubule boundary leads to distortion in determination of the calculated boundary. However, in tubulitis the lymphocytes and the tubule boundaries are proximate.In these cases the tubule boundary is adequately resolved and the image processing is satisfactory to determining relativity in location. An adaptive non-linear anisotropic diffusion process is presented for image filtering and segmentation. Multi-layer analysis is used to extract lymphocytes and tubulitis from images. This paper will discuss grading of tissue using the Banff system. The ability to use computer to use computer processing will be argued as obviating problems of reproducability of values for this classification. This paper will also feature discussion of alternative approaches to image processing and provide an assessment of their capability for improving the identification of the tubule boundaries.

  7. Monocytic Tissue Transglutaminase in a Rat Model for Reversible Acute Rejection and Chronic Renal Allograft Injury

    PubMed Central

    Zakrzewicz, Anna; Atanasova, Srebrena; Padberg, Winfried

    2015-01-01

    Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer-344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase-3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase-3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self-limiting acute rejection. PMID:26063971

  8. Effects of IFNγ administration on allograft rejection in ginbuna crucian carp.

    PubMed

    Shibasaki, Yasuhiro; Hatanaka, Chihiro; Matsuura, Yuta; Miyazawa, Ryuichiro; Yabu, Takeshi; Moritomo, Tadaaki; Nakanishi, Teruyuki

    2016-09-01

    In vertebrates, the rejection of allografts is primarily accomplished by cell-mediated immunity. We recently identified four IFNγ isoforms with antiviral activity in ginbuna crucian carp, Carassius auratus langsdorfii. However, involvement of the IFNγ isoforms in cell-mediated immunity, especially in T cell function remains unknown. Here we investigate expression of the IFNγ isoforms and effects of administration of recombinant IFNγ (rgIFNγ) isoforms in ginbuna scale allograft rejection. All four IFNγ isoforms showed significantly higher expression with the progression of graft rejection. Administration of rgIFNγrel 1 but not rgIFNγrel 2, rgIFNγ1 nor rgIFNγ2 enhanced allograft rejection. The number of CD4(+) and CD8α(+) cells increased in early stages of rejection, while sIgM(+) cells were higher than controls at day 0 and 5 in the rgIFNγrel 1 administrated group. Expression of IFNγ1 and IFNγ2 mRNA was significantly up-regulated by rgIFNγrel 1 administration, while that of IFNγrel 1 and IFNγrel 2 was not. These results suggest different contributions of the four IFNγ isoforms toward the immune responses comprising allograft rejection. PMID:27156851

  9. Monocyte procoagulant activity and plasminogen activator. Role in human renal allograft rejection

    SciTech Connect

    Cole, E.H.; Cardella, C.J.; Schulman, J.; Levy, G.A.

    1985-10-01

    Currently the mechanism of renal allograft rejection is not well understood. This study was designed to determine whether induction of monocyte procoagulant activity (MCPA) is important in the pathogenesis of renal allograft rejection. The MPCA assay was performed utilizing a one stage clotting assay both in normal and in factor-VII-deficient plasma. There was no increase in spontaneous MPCA in 20 patients with endstage renal failure and in 10 patients following abdominal or orthopedic operation, as compared with 20 normal controls. MPCA was assessed daily in 18 patients who had received renal allografts. Rejection episodes (RE) were predicted on the basis of persistent elevation in MPCA as compared with pretransplant levels. Rejection was diagnosed clinically and treated on the basis of standard criteria. Treated RE were compared with those predicted by elevated MPCA, and 3 patients were assessed as having no RE by MPCA and by standard criteria. In 8 RE, MPCA correlated temporally with RE (same day) when compared with standard criteria. In 12 RE, MPCA was predictive of rejection preceding standard criteria by at least 24 hr. There were 7 false-positive predictions on the basis of MPCA; however, there was only 1 false negative. MPCA was shown to be a prothrombinase by its dependence only on prothrombin and fibrinogen for full activity. MPCA may be important in the pathogenesis of allograft rejection, and additionally it may be a useful adjunct in the clinical management of this disease.

  10. Histopathology of cell mediated immune reaction in mouse colon--allograft rejection.

    PubMed Central

    Holden, R J; Ferguson, A

    1976-01-01

    Grafts of mouse fetal colon, implanted beneath the renal capsule of adult hosts, have been used to study the growth and development of colonic isografts and the rejection of colonic allografts. Isografts grew normally and maintained a structure similar to normal colon. Grafts between strains with H2 histocompatibility differences were rejected by 13 days after transplantation. Early progressive infiltration of the grafts by lymphoid cells was followed by increasing damage to, and subsequent loss of, the epithelial cell layer and destruction of the underlying muscle, changes which parallel those seen in rejection of skin and small bowel. The increase in survival time which is seen in allografts between strains with H2 identity was longer in the colon than has been seen in the skin or small bowel; none of the allografts of colon were completely rejected before 30 days, and some remained viable at 50 days. Comparison of the appearances of rejection in the colon with those of ulcerative colitis and colonic Crohn's disease does not show the striking similarity which is seen between small bowel rejection and coeliac disease. Many of the individual features of these diseases are, however, present in the course of colonic rejection. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:976806

  11. Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation

    PubMed Central

    Bourier, Felix; Kühne, Louisa; Banas, Miriam C.; Rümmele, Petra; Wurm, Simone; Banas, Bernhard

    2016-01-01

    Objective Despite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation. Results Macrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival. Conclusion The differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis

  12. Use of indium-111-labeled cells in measurement of cellular dynamics of experimental cardiac allograft rejection

    SciTech Connect

    Oluwole, S.; Wang, T.; Fawwaz, R.; Satake, K.; Nowygrod, R.; Reemtsma, K.; Hardy, M.A.

    1981-01-01

    This study evaluates the kinetics and utility of infused indium-111-labeled cells in detecting rejection in ACI to Lewis rat heart allografts. Syngeneic leukocytes, lymph node lymphocytes, and platelets were isolated and labeled with indium-111 (/sup 111/In) oxine, respectively, and were infused i.v. into Lewis rats carrying beating ACI or syngeneic hearts from post-transplant days 0 to 6. Recipients were imaged serially at 24 hr after infusion of labeled cells followed by excision of both native and transplanted hearts for direct isotope count. Labeled leukocytes accumulative progressively in the allograft with the scan becoming positive by post-transplant day 4. The ratio of allograft to native heart isotope counts rose from 1.25 on day 1 to 10.07 (P less than 0.0001) on day 7. The Lewis recipients infused with labeled lymphocytes showed a positive scan on days 6 and 7 whereas the allograft to native heart isotope count ratio rose from 0.97 on day 1 to 5.33 (P less than 0.001) on day 7. Recipients infused with /sup 111/In-labeled platelets showed a positive scan on days 5 to 7 and the allograft to native heart isotope count ratio rose sharply from 2.56 on day 4 to 16.98 (P less than 0.005) on day 7. Syngeneic heart grafts failed to demonstrate significant accumulation of any of the labeled cell population. These studies confirm the importance of nonlymphocytic cells in cellular rejection, evaluate the kinetics of graft invasion by the various cell types, and suggest that the techniques used afford a method for a safe and an early detection of allograft rejection.

  13. Perforin and granzyme B. Cytolytic proteins up-regulated during rejection of rat small intestine allografts.

    PubMed

    McDiarmid, S V; Farmer, D G; Kuniyoshi, J S; Robert, M; Khadavi, A; Shaked, A; Busuttil, R W

    1995-03-15

    Perforin and granzyme B are 2 cytolytic proteins specific to activated killer cells, particularly CTL. We have studied the mRNA expression of these 2 proteins by a reverse transcriptase polymerase chain reaction method in a unidirectional model of rat small intestine transplant rejection. The allograft group consisted of Lewis x Brown Norway F1 donors into Lewis recipients. The isograft controls were Lewis donors into Lewis recipients. Grafts were placed heterotopically and no immunosuppression was given. Five animals in each group were killed at postoperative days (POD) 3, 5, 7, 8, 9, 10, 12, and 14. mRNA was extracted and a semiquantitative reverse transcriptase polymerase chain reaction was performed. For the semiquantitative analysis, we compared scintillation counts from excised bands. Results were expressed as a percent activity compared with beta-actin. From the same tissue samples, a histologic evaluation was made and rejection was graded according to severity. The isograft controls showed no evidence of histologic rejection and a very low expression of mRNA for perforin and granzyme B from POD 3-14. In contrast, the allograft group began to show histologic evidence of mild rejection on POD 5. By day 7, rejection was moderately severe and associated with a significant up-regulation of perforin and granzyme B in the allografts compared with the controls (P < 0.01), which persisted through POD 14. Peak expression for perforin and granzyme B was on POD 10 and 8, respectively. We conclude that the up-regulation of perforin and granzyme B in rat small intestine transplant allografts is a useful marker of clinically important rejection. PMID:7886805

  14. Detection of rejection of canine orthotopic cardiac allografts with indium-111 lymphocytes and gamma scintigraphy

    SciTech Connect

    Eisen, H.J.; Rosenbloom, M.; Laschinger, J.C.; Saffitz, J.E.; Cox, J.L.; Sobel, B.E.; Bolman, R.M. III; Bergmann, S.R.

    1988-07-01

    Previous studies have demonstrated the feasibility of detecting canine heterotopic cardiac allograft rejection scintigraphically after administration of 111In lymphocytes. To determine whether the approach is capable of detecting rejection in orthotopic cardiac transplants in which labeled lymphocytes circulating in the blood pool may reduce sensitivity, the present study was performed in which canine orthotopic cardiac transplants were evaluated in vivo. Immunosuppression was maintained with cyclosporine A (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 2 wk after transplantation. Subsequently, therapy was tapered. Five successful allografts were evaluated scintigraphically every 3 days after administration of 100-350 microCi 111In autologous lymphocytes. Correction for labeled lymphocytes circulating in the blood pool, but not actively sequestered in the allografts was accomplished by administering 3-6 mCi 99mTc autologous erythrocytes and employing a previously validated blood-pool activity correction technique. Cardiac infiltration of labeled lymphocytes was quantified as percent indium excess (%IE), scintigraphically detectable 111In in the transplant compared with that in blood, and results were compared with those of concomitantly performed endomyocardial biopsy. Scintigraphic %IE for hearts not undergoing rejection manifest histologically was 0.7 +/- 0.4. Percent IE for rejecting hearts was 6.8 +/- 4.0 (p less than 0.05). Scintigraphy detected each episode of rejection detected by biopsy. Scintigraphic criteria for rejection (%IE greater than 2 s.d. above normal) were not manifest in any study in which biopsies did not show rejection. Since scintigraphic results with 111In-labeled lymphocytes were concordant with biopsy results in orthotopic cardiac transplants, noninvasive detection of graft rejection in patients should be attainable with the approach developed.

  15. Use of [18F]FDG PET to Monitor The Development of Cardiac Allograft Rejection

    PubMed Central

    Daly, Kevin P.; Dearling, Jason L. J.; Seto, Tatsuichiro; Dunning, Patricia; Fahey, Frederic; Packard, Alan B.; Briscoe, David M.

    2014-01-01

    Background Positron Emission Tomography (PET) has the potential to be a specific, sensitive and quantitative diagnostic test for transplant rejection. To test this hypothesis, we evaluated 18F-labeled fluorodeoxyglucose ([18F]FDG) and 13N-labeled ammonia ([13N]NH3) small animal PET imaging in a well-established murine cardiac rejection model. Methods Heterotopic transplants were performed using minor MHC mismatched B6.C-H2bm12 donor hearts in C57BL/6(H-2b) recipients. C57BL/6 donor hearts into C57BL/6 recipients served as isograft controls. [18F]FDG PET imaging was performed weekly between post-transplant days 7 and 42 and the percent injected dose was computed for each graft. [13N]NH3 imaging was performed to evaluate myocardial perfusion. Results There was a significant increase in [18F]FDG uptake in allografts from day 14 to day 21 (1.6% to 5.2%; P<0.001) and uptake in allografts was significantly increased on post-transplant days 21 (5.2% vs. 0.9%; P=0.005) and 28 (4.8% vs. 0.9%; P=0.006) compared to isograft controls. Furthermore, [18F]FDG uptake correlated with an increase in rejection within allografts between days 14 and 28 post-transplant. Finally, the uptake of [13N]NH3 was significantly lower relative to the native heart in allografts with chronic vasculopathy compared to isograft controls on day 28 (P=0.01). Conclusions PET imaging with [18F]FDG can be used following transplantation to monitor the evolution of rejection. In addition, decreased uptake of [13N]NH3 in rejecting allografts may be reflective of decreased myocardial blood flow. These data suggest that combined [18F]FDG and [13N]NH3 PET imaging could be used as a non-invasive, quantitative technique for serial monitoring of allograft rejection and has potential application in human transplant recipients. PMID:25675207

  16. Nitric oxide formation in acutely rejecting cardiac allografts correlates with GTP cyclohydrolase I activity

    PubMed Central

    2005-01-01

    Inducible nitric oxide synthase (iNOS) is a prominent component of the complex array of mediators in acute graft rejection. While NO production is determined by iNOS expression, BH4 (tetrahydrobiopterin), a cofactor of iNOS synthesized by GTP cyclohydrolase I, has been considered critical in sustaining NO production. In the present study, we examined time-dependent changes in iNOS and GTP cyclohydrolase I in rat cardiac allografts. The increase in iNOS protein and mRNA in allografts was similar at POD4 (post-operative day 4) and POD6. However, the peak increase in intragraft NO level at POD4 was not sustained at POD6. This disparity could not be explained by any decrease in iNOS enzyme activity measured ex vivo with optimal amounts of substrate and cofactors. Lower iNOS activity could be explained by changes in total biopterin levels in allografts at POD4 that was decreased to baseline at POD6. Changes in biopterin production correlated with lower GTP cyclohydrolase I protein levels but not by any change in GTP cyclohydrolase I mRNA. Functionally, allografts displayed bradycardia and distended diastolic and systolic dimensions at POD6 but not at POD4. Likewise, histological rejection scores were increased at POD4 but with a secondary increased stage at POD6. It is hypothesized that the dissimilar amounts of NO at early and later stages of rejection is due to uncoupling of iNOS arising from disproportionate synthesis of BH4. These findings provide insight into a potential pathway regulating NO bioactivity in graft rejection. Such knowledge may potentially assist in the design of newer strategies to prevent acute graft rejection. PMID:16000090

  17. Liver allograft rejection in sensitized recipients. Observations in a clinically relevant small animal model.

    PubMed Central

    Nakamura, K.; Murase, N.; Becich, M. J.; Furuya, T.; Todo, S.; Fung, J. J.; Starzl, T. E.; Demetris, A. J.

    1993-01-01

    A sequential analysis of liver allograft rejection in sensitized rats using immunopathological and ultrastructural microscopy is described. Lewis rats were primed with four ACI skin grafts and challenged with an arterialized ACI orthotopic liver allograft 14 to 17 weeks later. The sensitization resulted in a mix of IgG and IgM lymphocytotoxic antibodies at a titer of 1:512 at the time of transplantation. Specificity analysis of pretransplant immune sera revealed a predominance of IgG anti-class I major histocompatibility complex (RT1) antibodies with a minor IgG fraction showing apparent endothelial cell specificity (non-RT1). This level of sensitization was associated with accelerated graft failure in 3 to 5 days from mixed humoral and cellular rejection. Sequential analysis of serial posttransplant graft biopsies revealed diffuse vascular IgG deposition and platelet thrombi in portal veins and periportal sinusoids within 3 minutes after reperfusion. This was followed by endothelial cell hypertrophy and vacuolization, periportal hepatocyte necrosis, arterial spasm, focal large bile duct necrosis, and hilar mast cell infiltration and degranulation. However, the liver allografts did not fail precipitously and hyperacute rejection was not seen. Kupffer cell phagocytosis of the sinusoidal platelets began as early as 30 minutes posttransplant and by 24 hours, the platelet thrombi had decreased. Cholangioles appeared focally at the edge of the limiting plates by 2 to 3 days, apparently in response to earlier periportal hepatocyte damage. A mononuclear portal and perivenular infiltrate became evident at 3 days, and graft failure was attributed to both antibody and cell-mediated rejection (Furuya et al: Preformed lymphocytotoxic antibodies: Hepatology 1992, 16: 1415-1422). The model described resembles observations in crossmatch positive human liver allograft recipients. The mechanisms of hepatic graft resistance to antibody mediated rejection and the possible long term

  18. Ischemia-Reperfusion Injury Enhances Lymphatic Endothelial VEGFR3 and Rejection in Cardiac Allografts.

    PubMed

    Dashkevich, A; Raissadati, A; Syrjälä, S O; Zarkada, G; Keränen, M A I; Tuuminen, R; Krebs, R; Anisimov, A; Jeltsch, M; Leppänen, V-M; Alitalo, K; Nykänen, A I; Lemström, K B

    2016-04-01

    Organ damage and innate immunity during heart transplantation may evoke adaptive immunity with serious consequences. Because lymphatic vessels bridge innate and adaptive immunity, they are critical in immune surveillance; however, their role in ischemia-reperfusion injury (IRI) in allotransplantation remains unknown. We investigated whether the lymphangiogenic VEGF-C/VEGFR3 pathway during cardiac allograft IRI regulates organ damage and subsequent interplay between innate and adaptive immunity. We found that cardiac allograft IRI, within hours, increased graft VEGF-C expression and lymphatic vessel activation in the form of increased lymphatic VEGFR3 and adhesion protein expression. Pharmacological VEGF-C/VEGFR3 stimulation resulted in early lymphatic activation and later increase in allograft inflammation. In contrast, pharmacological VEGF-C/VEGFR3 inhibition during cardiac allograft IRI decreased early lymphatic vessel activation with subsequent dampening of acute and chronic rejection. Genetic deletion of VEGFR3 specifically in the lymphatics of the transplanted heart recapitulated the survival effect achieved by pharmacological VEGF-C/VEGFR3 inhibition. Our results suggest that tissue damage rapidly changes lymphatic vessel phenotype, which, in turn, may shape the interplay of innate and adaptive immunity. Importantly, VEGF-C/VEGFR3 inhibition during solid organ transplant IRI could be used as lymphatic-targeted immunomodulatory therapy to prevent acute and chronic rejection. PMID:26689983

  19. Inhibition of Chemokine-Glycosaminoglycan Interactions in Donor Tissue Reduces Mouse Allograft Vasculopathy and Transplant Rejection

    PubMed Central

    Dai, Erbin; Liu, Li-Ying; Wang, Hao; McIvor, Dana; Sun, Yun ming; Macaulay, Colin; King, Elaine; Munuswamy-Ramanujam, Ganesh; Bartee, Mee Yong; Williams, Jennifer; Davids, Jennifer; Charo, Israel; McFadden, Grant; Esko, Jeffrey D.; Lucas, Alexandra R.

    2010-01-01

    chemokine-receptor blockade, is a highly effective approach to reduction of allograft rejection, reducing vascular inflammation and prolonging allograft survival. Although chemokines direct both local and systemic cell migration, interruption of inherent chemokine responses in the donor tissue unexpectedly had a greater therapeutic impact on allograft vasculopathy. PMID:20463901

  20. Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site

    PubMed Central

    Ben Nasr, Moufida; Vergani, Andrea; Avruch, James; Liu, Liye; Kefaloyianni, Eirini; D’Addio, Francesca; Tezza, Sara; Corradi, Domenico; Bassi, Roberto; Valderrama-Vasquez, Alessandro; Usuelli, Vera; Kim, James; Azzi, Jamil; Essawy, Basset El; Markmann, James; Abdi, Reza

    2016-01-01

    Aims Mesenchymal stem cells (MSCs) are multipotent cells with immunomodulatory properties. We tested the ability of MSCs to delay islet allograft rejection. Methods Mesenchymal stem cells were generated in vitro from C57BL/6 and BALB/c mice bone marrow, and their immunomodulatory properties were tested in vitro. We then tested the effect of a local or systemic administration of heterologous and autologous MSCs on graft survival in a fully allogeneic model of islet transplantation (BALB/c islets into C57BL/6 mice). Results In vitro, autologous, but not heterologous, MSCs abrogated immune cell proliferation in response to alloantigens and skewed the immune response toward a Th2 profile. A single dose of autologous MSCs co-transplanted under the kidney capsule with allogeneic islets delayed islet rejection, reduced graft infiltration, and induced long-term graft function in 30 % of recipients. Based on ex vivo analysis of recipient splenocytes, the use of autologous MSCs did not appear to have any systemic effect on the immune response toward graft alloantigens. The systemic injection of autologous MSCs or the local injection of heterologous MSCs failed to delay islet graft rejection. Conclusion Autologous, but not heterologous, MSCs showed multiple immunoregulatory properties in vitro and delayed allograft rejection in vivo when co-transplanted with islets; however, they failed to prevent rejection when injected systemically. Autologous MSCs thus appear to produce a local immunoprivileged site, which promotes graft survival. PMID:25808641

  1. Nitration and Inactivation of Manganese Superoxide Dismutase in Chronic Rejection of Human Renal Allografts

    NASA Astrophysics Data System (ADS)

    MacMillan-Crow, L. A.; Crow, John P.; Kerby, Jeffrey D.; Beckman, Joseph S.; Thompson, John A.

    1996-10-01

    Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 μ M) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria.

  2. MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

    SciTech Connect

    Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao; Wu, William K.K.; Chan, Matthew T.V.; Zhang, Jie; Li, Haibin; Qin, Ke; Sun, Xuyong

    2015-04-10

    Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, and chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.

  3. Sensitized recipients exhibit accelerated but not hyperacute rejection of vascularized composite tissue allografts1

    PubMed Central

    Wu, Shengli; Xu, Hong; Chen, Bo; Wen, Yujie; Ikusika, Olayemi M; Ocker, Ashley; Zhao, Hong; Ildstad, Suzanne T

    2013-01-01

    Background Currently, the donor-recipient matching process for vascularized composite tissue allotransplantation (VCTA) closely follows the standard practices for solid organ transplantation. Sensitization is considered a contraindication to VCTA. However, the role of sensitization in VCTA rejection is largely unstudied. Methods Major histocompatibility-mismatched ACI (RT1a) donors and WF (RT1u) recipients were used to determine if sensitization would lead to hyperacute rejection in VCTA as in other organs, such as kidneys. WF rats were presensitized to ACI antigens by skin transplantation and received heterotopic osteomyocutaneous VCTA flaps. Kidney transplants served as controls. Results Production of anti-donor antibody was detected in WF recipients after rejection of the ACI skin grafts. Sensitized WF rats rejected VCTA grafts from ACI rats significantly faster (P < 0.05) than unsensitized recipients, but not hyperacutely. Rejection in the sensitized recipients was not prevented by immunosuppression with FK506 and mycophenolate mofetil. In contrast, kidney allografts from ACI rats were hyperacutely rejected within 30 minutes by sensitized recipients. To confirm the role of antibody-mediated rejection in the sensitized recipients, serum from presensitized rats was adoptively transferred into naïve WF rats. Hyperacute rejection occurred only in transplanted kidneys but not VCTA. Histological examination of tissues from acceleratedly rejected VCTA showed dense lymphocytic infiltrates, and no antibody deposition. Conclusions VCTA are rejected in an accelerated fashion but not hyperacutely in the presence of allosensitization and preformed anti-donor antibody. The rejection of VCTA in sensitized recipients is mainly cell-mediated and differs mechanistically from that for renal transplants. PMID:21822173

  4. Subclinical Rejection Phenotypes at 1 Year Post-Transplant and Outcome of Kidney Allografts.

    PubMed

    Loupy, Alexandre; Vernerey, Dewi; Tinel, Claire; Aubert, Olivier; Duong van Huyen, Jean-Paul; Rabant, Marion; Verine, Jérôme; Nochy, Dominique; Empana, Jean-Philippe; Martinez, Frank; Glotz, Denis; Jouven, Xavier; Legendre, Christophe; Lefaucheur, Carmen

    2015-07-01

    Kidney allograft rejection can occur in clinically stable patients, but long-term significance is unknown. We determined whether early recognition of subclinical rejection has long-term consequences for kidney allograft survival in an observational prospective cohort study of 1307 consecutive nonselected patients who underwent ABO-compatible, complement-dependent cytotoxicity-negative crossmatch kidney transplantation in Paris (2000-2010). Participants underwent prospective screening biopsies at 1 year post-transplant, with concurrent evaluations of graft complement deposition and circulating anti-HLA antibodies. The main analysis included 1001 patients. Three distinct groups of patients were identified at the 1-year screening: 727 (73%) patients without rejection, 132 (13%) patients with subclinical T cell-mediated rejection (TCMR), and 142 (14%) patients with subclinical antibody-mediated rejection (ABMR). Patients with subclinical ABMR had the poorest graft survival at 8 years post-transplant (56%) compared with subclinical TCMR (88%) and nonrejection (90%) groups (P<0.001). In a multivariate Cox model, subclinical ABMR at 1 year was independently associated with a 3.5-fold increase in graft loss (95% confidence interval, 2.1 to 5.7) along with eGFR and proteinuria (P<0.001). Subclinical ABMR was associated with more rapid progression to transplant glomerulopathy. Of patients with subclinical TCMR at 1 year, only those who further developed de novo donor-specific antibodies and transplant glomerulopathy showed higher risk of graft loss compared with patients without rejection. Our findings suggest that subclinical TCMR and subclinical ABMR have distinct effects on long-term graft loss. Subclinical ABMR detected at the 1-year screening biopsy carries a prognostic value independent of initial donor-specific antibody status, previous immunologic events, current eGFR, and proteinuria. PMID:25556173

  5. Lentivirus IL-10 gene therapy down-regulates IL-17 and attenuates mouse orthotopic lung allograft rejection.

    PubMed

    Hirayama, S; Sato, M; Loisel-Meyer, S; Matsuda, Y; Oishi, H; Guan, Z; Saito, T; Yeung, J; Cypel, M; Hwang, D M; Medin, J A; Liu, M; Keshavjee, S

    2013-06-01

    The purpose of the study was to examine the effect of lentivirus-mediated IL-10 gene therapy to target lung allograft rejection in a mouse orthotopic left lung transplantation model. IL-10 may regulate posttransplant immunity mediated by IL-17. Lentivirus-mediated trans-airway luciferase gene transfer to the donor lung resulted in persistent luciferase activity up to 6 months posttransplant in the isograft (B6 to B6); luciferase activity decreased in minor-mismatched allograft lungs (B10 to B6) in association with moderate rejection. Fully MHC-mismatched allograft transplantation (BALB/c to B6) resulted in severe rejection and complete loss of luciferase activity. In minor-mismatched allografts, IL-10-encoding lentivirus gene therapy reduced the acute rejection score compared with the lentivirus-luciferase control at posttransplant day 28 (3.0 ± 0.6 vs. 2.0 ± 0.6 (mean ± SD); p = 0.025; n = 6/group). IL-10 gene therapy also significantly reduced gene expression of IL-17, IL-23, and retinoic acid-related orphan receptor (ROR)-γt without affecting levels of IL-12 and interferon-γ (IFN-γ). Cells expressing IL-17 were dramatically reduced in the allograft lung. In conclusion, lentivirus-mediated IL-10 gene therapy significantly reduced expression of IL-17 and other associated genes in the transplanted allograft lung and attenuated posttransplant immune responses after orthotopic lung transplantation. PMID:23601206

  6. Antibody Mediated Rejection as a Contributor to Previously Unexplained Early Liver Allograft Loss

    PubMed Central

    O’Leary, Jacqueline G.; Kaneku, Hugo; Demetris, Anthony J.; Marr, John D.; Shiller, S. Michelle; Susskind, Brian M.; Tillery, Glenn W.; Terasaki, Paul I.; Klintmalm, Göran B.

    2015-01-01

    We analyzed 60 patients with idiopathic early allograft loss (defined as death or retransplantation <90 days) to determine the relative contribution of preformed donor specific HLA alloantibodies (DSA) to this endpoint and defined strict criteria for the diagnosis of antibody-mediated rejection (AMR) in liver allografts. Inclusion criteria encompassed availability of a pre-transplant serum sample and both post-reperfusion and follow-up tissue specimens for “blinded” retrospective re-review of histology and C4d staining. AMR was diagnosed based on the presence of all 4 strict criteria: 1) DSA in serum; 2) histopathological evidence of diffuse microvascular injury/microvasculitis, consistent with antibody-mediated injury; 3) diffuse C4d staining in the portal microvasculature with or without staining in the sinusoids or central veins in at least one sample; and 4) exclusion of other causes of a similar type of injury. Patients thought to be experiencing definite AMR on the basis of routine histopathology alone showed the highest levels of DSA sensitization. Forty percent of patients with pre-transplant DSA with a pattern of bead saturation after serial dilutions developed AMR. One additional multiparous female developed, what appeared to be, a strong “recall” response resulting in combined AMR and ACR causing graft failure. A contribution of DSA to allograft failure could not be excluded in three additional patients who received marginal grafts. In conclusion, liver allograft recipients with high mean fluorescence intensity (MFI) preformed DSA despite dilution seem to be at risk for clinically significant allograft injury, and possibly loss, from AMR often in combination with ACR. PMID:24382837

  7. Rejection of cardiac allografts by T cells expressing a restricted repertoire of T-cell receptor V beta genes.

    PubMed Central

    Shirwan, H; Barwari, L; Cramer, D V

    1997-01-01

    We have recently shown that T cells infiltrating cardiac allografts early in graft rejection use a limited T-cell receptor (TCR) V beta repertoire. In this study we tested whether this limited repertoire of V beta genes is important for graft rejection. A cell line, AL2-L3, was established from LEW lymphocytes infiltrating ACI heart allografts 2 days after transplantation. This cell line is composed of CD4+ T cells that primarily recognize the class II RTI.B major histocompatibility complex (MHC) molecule expressed by the donor graft. This cell line precipitated acute rejection of donor hearts with a median survival time (MST) of 10.5 days following adoptive transfer to sublethally irradiated LEW recipients. This rate of graft rejection was significantly (P < 0.0007) accelerated when compared with a MST of 60 days for allografts in irradiated control recipients. The AL2-L3-mediated acceleration of graft rejection was donor specific as WF third-party heart allografts were rejected with a delayed tempo (MST = 28.5 days). The V beta repertoire of this cell line was primarily restricted to the expression of V beta 4, 15 and 19 genes. The nucleotide sequence analysis of the beta-chain cDNAs from this cell line demonstrated that the restricted use of the V gene repertoire was not shared with the N, D and J regions. A wide variety of CDR3 loops and J beta genes were used in association with selected V beta genes. These data provide evidence for the role a restricted repertoire of V beta genes plays in cardiac allograft rejection in this model. The restricted usage of the V beta repertoire in an early T-cell response to allografts may provide the opportunity to therapeutically disrupt the rejection reaction by targeting selected T-cell populations for elimination at the time of organ transplantation. Images Figure 2 PMID:9176111

  8. Indirect recognition of MHC class I allopeptides accelerates lung allograft rejection in miniature swine.

    PubMed

    Shoji, Tsuyoshi; Wain, John C; Houser, Stuart L; Benjamin, Louis C; Johnston, Douglas R; Hoerbelt, Ruediger; Hasse, Rebecca S; Lee, Richard S; Muniappan, Ashok; Guenther, Dax A; Bravard, Marjory A; Ledgerwood, Levi G; Sachs, David H; Sayegh, Mohamed H; Madsen, Joren C; Allan, James S

    2005-07-01

    The role of indirect allorecognition in graft rejection is examined in two experiments using a swine lung transplantation model. First, two swine received class I mismatched grafts without immunosuppression; another two recipients were treated postoperatively with cyclosporine (CsA). These swine exhibited acute and chronic rejection, respectively. All four recipients developed T-cell reactivity to donor-derived class I major histocompatibility complex (MHC) peptides. Second, six swine were immunized with synthetic donor-derived class I allopeptides prior to transplantation. Control groups consisted of nonimmunized recipients (n = 6) and recipients immunized with an irrelevant peptide (n = 3). These recipients all received a 12-day course of post-operative CsA. Swine immunized with allopeptides exhibited accelerated graft rejection, as compared to both control groups (p < 0.01 and p = 0.03, respectively). Within the experimental group, the dominant histologic finding was acute rejection (AR). Obliterative bronchiolitis (OB) was seen in the graft with the longest survival. Both control groups showed a lesser degree of AR, with four out of six nonimmunized swine ultimately developing OB. These studies suggest that indirect allorecognition is operative during lung allograft rejection, and that pre-transplant sensitization to donor-derived MHC allopeptides can accelerate graft rejection. PMID:15943620

  9. 19F MRI detection of acute allograft rejection with in vivo perfluorocarbon labeling of immune cells.

    PubMed

    Hitchens, T Kevin; Ye, Qing; Eytan, Danielle F; Janjic, Jelena M; Ahrens, Eric T; Ho, Chien

    2011-04-01

    Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure.We have previously shown that cellular magnetic resonance imaging (MRI) of iron-oxide labeled immune-cell infiltration can provide a noninvasive measure of rejection status by detecting areas of hypointensity on T 2*-weighted images. In this study, we tested the feasibility of using a fluorine-based cellular tracer agent to detect macrophage accumulation in rodent models of acute allograft rejection by fluorine-19 ((19) F) MRI and magnetic resonance spectroscopy. This study used two rat models of acute rejection, including abdominal heterotopic cardiac transplant and orthotopic kidney transplant models. Following in vivo labeling of monocytes and macrophages with a commercially available agent containing perfluoro-15-crown-5-ether, we observed (19) F-signal intensity in the organs experiencing rejection by (19) F MRI, and conventional (1) H MRI was used for anatomical context. Immunofluorescence and histology confirmed macrophage labeling. These results are consistent with our previous studies and show the complementary nature of the two cellular imaging techniques. With no background signal, (19) F MRI/magnetic resonance spectroscopy can provide unambiguous detection of fluorine labeled cells, and may be a useful technique for detecting and quantifying rejection grade in patients. PMID:21305593

  10. Suppression of allograft rejection in the sponge Suberites domuncula by FK506 and expression of genes encoding FK506-binding proteins in allografts.

    PubMed

    Müller, W E; Steffen, R; Lorenz, B; Batel, R; Kruse, M; Krasko, A; Müller, I M; Schröder, H C

    2001-07-01

    Porifera (sponges) are, evolutionarily, the oldest metazoan phylum. Recent molecular data suggest that these animals possess molecules similar to and homologous with those of the innate and adaptive immune systems of higher Metazoa. Applying the biological system of parabiosis and the technique of differential display of mRNA, two cDNAs encoding putative FK506-binding proteins were isolated. FK506 is successfully used in clinics as a drug to prevent allograft rejection and is toxic to Suberites domuncula cells in vitro at doses above 100ng ml(-1). Autograft fusion of transplants from S. domuncula was not affected by FK506. Allograft non-fusion was not affected by FK506 at toxic doses; however, at the non-toxic dose of 20ng ml(-1), the allografts fused with each other. It is shown that at the attachment zone in untreated and (particularly drastic) in FK506-treated allografts, expression of the genes encoding the FK506-binding proteins is upregulated. These data indicate that the drug FK506 suppresses allograft rejection in S. domuncula, most probably via interaction with expression of the gene coding for the FK506-binding proteins. PMID:11507104

  11. Corticosteroid-loaded biodegradable nanoparticles for prevention of corneal allograft rejection in rats.

    PubMed

    Pan, Qing; Xu, Qingguo; Boylan, Nicholas J; Lamb, Nicholas W; Emmert, David G; Yang, Jeh-Chang; Tang, Li; Heflin, Tom; Alwadani, Saeed; Eberhart, Charles G; Stark, Walter J; Hanes, Justin

    2015-03-10

    Immunologic graft rejection is one of the main causes of short and long-term graft failure in corneal transplantation. Steroids are the most commonly used immunosuppressive agents for postoperative management and prevention of corneal graft rejection. However, steroids delivered in eye drops are rapidly cleared from the surface of the eye, so the required frequency of dosing for corneal graft rejection management can be as high as once every 2h. Additionally, these eye drops are often prescribed for daily use for 1 year or longer, which can result in poor patient compliance and steroid-related side effects. Here, we report a biodegradable nanoparticle system composed of Generally Regarded as Safe (GRAS) materials that can provide sustained release of corticosteroids to prevent corneal graft rejection following subconjunctival injection provided initially during transplant surgery. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing dexamethasone sodium phosphate (DSP) exhibited a size of 200 nm, 8 wt.% drug loading, and sustained drug release over 15 days in vitro under sink conditions. DSP-loaded nanoparticles provided sustained ocular drug levels for at least 7 days after subconjunctival administration in rats, and prevented corneal allograft rejection over the entire 9-week study when administered weekly. In contrast, control treatment groups that received weekly injections of either placebo nanoparticles, saline, or DSP in solution demonstrated corneal graft rejection accompanied by severe corneal edema, neovascularization and opacity that occurred in ≤ 4 weeks. Local controlled release of corticosteroids may reduce the rate of corneal graft rejection, perhaps especially in the days immediately following surgery when risk of rejection is highest and when typical steroid eye drop administration requirements are particularly onerous. PMID:25576786

  12. Both rejection and tolerance of allografts can occur in the absence of secondary lymphoid tissues.

    PubMed

    Kant, Cavit D; Akiyama, Yoshinobu; Tanaka, Katsunori; Shea, Susan; Yamada, Yohei; Connolly, Sarah E; Marino, Jose; Tocco, Georges; Benichou, Gilles

    2015-02-01

    In this study, we showed that aly/aly mice, which are devoid of lymph nodes and Peyer's patches, acutely rejected fully allogeneic skin and heart grafts. They mounted potent inflammatory direct alloresponses but failed to develop indirect alloreactivity after transplantation. Remarkably, skin allografts also were rejected acutely by splenectomized aly/aly (aly/aly-spl(-)) mice devoid of all secondary lymphoid organs. In these recipients, the rejection was mediated by alloreactive CD8(+) T cells presumably primed in the bone marrow. In contrast, cardiac transplants were not rejected by aly/aly-spl(-) mice. Actually, aly/aly-spl(-) mice that spontaneously accepted a heart allotransplant and displayed donor-specific tolerance also accepted skin grafts from the same, but not a third-party, donor via a mechanism involving CD4(+) regulatory T cells producing IL-10 cytokine. Therefore, direct priming of alloreactive T cells, as well as rejection and regulatory tolerance of allogeneic transplants, can occur in recipient mice lacking secondary lymphoid organs. PMID:25535285

  13. Arsenic trioxide attenuated the rejection of major histocompatibility complex fully-mismatched cardiac allografts in mice.

    PubMed

    Yan, S; Zhang, Q Y; Zhou, B; Xue, L; Chen, H; Wang, Y; Zheng, S S

    2009-06-01

    We investigated the effects of arsenic trioxide (As(2)O(3)) on allogeneic immune response using a mouse heart transplantation model. Mice were randomly divided into 4 groups of 6 animals each. The control group received phosphate-buffered saline (PBS); the As(2)O(3)-treated group, intraperitoneal (IP) injection of As(2)O(3) (1 mg/kg) from days -3 to 10 after heart transplantation. The cyclosporine (CsA)-treated group was given a subtherapeutic dose of CsA (10 mg/kg) IP, and the As(2)O(3) plus CsA-treated group, a combined protocol of As(2)O(3) and CsA. Six days after transplantation, cardiac allografts were harvested for immunohistology and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The survival of the allografts was significantly improved among the As(2)O(3)-treated group compared with the control group (17.2 +/- 1.9 vs 8.0 +/- 0.9 days; P < .05). A marked prolongation (28.6 +/- 6.0 days) of graft survival was achieved by the combined protocol compared with the CsA-treated group (9.6 +/- 3.0 days; P < .05) or the As(2)O(3)-treated group. Allografts of As(2)O(3)-treated and As(2)O(3) plus CsA-treated mice showed a changing pattern of Th1/Th2 cytokine mRNA expression. Allograft rejection was apparently alleviated by low-dose As(2)O(3), and particularly when combined with a subtherapeutic CsA dose. PMID:19545743

  14. Gene-based bio-signature patterns and cardiac allograft rejection.

    PubMed

    Mehra, Mandeep R; Uber, Patricia A; Benitez, Roberto M

    2010-01-01

    Clinicians have long awaited an alternative to invasive endomyocardial biopsy for surveillance of cardiac transplant rejection. Transcriptional signals in peripheral blood mononuclear cells allow for the development of multigene-based panels that can inform on the presence or absence of immunologic quiescence. The informative genes represent several biologic pathways, including T-cell activation (PDCD1), T-cell migration (ITGA4), and mobilization of hematopoietic precursors (WDR40A and microRNA gene family cMIR), and steroid-responsive genes such as IL1R2, the decoy receptor for interleukin 2. The greatest value may include the ability to inform on the potential of future proclivity for rejection, allowing patients to be stratified into low, intermediate, or high risk subsets for future rejection. In these individuals, this knowledge may allow clinicians to use tailored approaches to immunosuppression, thereby avoiding adverse pharmacologic effects in low-risk patients while improving rejection outcomes in those at high risk for future allograft compromise. Despite these advances, clinical entrenchment of gene-based pharmacotherapy in cardiac transplantation will require independent replication and validation of investigational findings. PMID:19945064

  15. CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection

    PubMed Central

    Harper, Simon J. F.; Ali, Jason M.; Wlodek, Elizabeth; Negus, Marg C.; Harper, Ines G.; Chhabra, Manu; Qureshi, M. Saeed; Mallik, Mekhola; Bolton, Eleanor; Bradley, J. Andrew; Pettigrew, Gavin J.

    2015-01-01

    Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen “indirectly,” as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are “unlinked” on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the “semidirect” pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell–mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation. PMID:26420874

  16. Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

    PubMed

    Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

    2015-01-01

    Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation. PMID:26335204

  17. Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection

    PubMed Central

    Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

    2015-01-01

    Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation. PMID:26335204

  18. Follicular Helper T (Tfh) Cells in Autoimmune Diseases and Allograft Rejection.

    PubMed

    Jeon, Yun-Hui; Choi, Youn Soo

    2016-08-01

    Production of high affinity antibodies for antigens is a critical component for the immune system to fight off infectious pathogens. However, it could be detrimental to our body when the antigens that B cells recognize are of self-origin. Follicular helper T, or Tfh, cells are required for the generation of germinal center reactions, where high affinity antibody-producing B cells and memory B cells predominantly develop. As such, Tfh cells are considered as targets to prevent B cells from producing high affinity antibodies against self-antigens, when high affinity autoantibodies are responsible for immunopathologies in autoimmune disorders. This review article provides an overview of current understanding of Tfh cells and discusses it in the context of animal models of autoimmune diseases and allograft rejections for generation of novel therapeutic interventions. PMID:27574501

  19. Follicular Helper T (Tfh) Cells in Autoimmune Diseases and Allograft Rejection

    PubMed Central

    Jeon, Yun-Hui

    2016-01-01

    Production of high affinity antibodies for antigens is a critical component for the immune system to fight off infectious pathogens. However, it could be detrimental to our body when the antigens that B cells recognize are of self-origin. Follicular helper T, or Tfh, cells are required for the generation of germinal center reactions, where high affinity antibody-producing B cells and memory B cells predominantly develop. As such, Tfh cells are considered as targets to prevent B cells from producing high affinity antibodies against self-antigens, when high affinity autoantibodies are responsible for immunopathologies in autoimmune disorders. This review article provides an overview of current understanding of Tfh cells and discusses it in the context of animal models of autoimmune diseases and allograft rejections for generation of novel therapeutic interventions. PMID:27574501

  20. Clinical relevance of circulating antibodies and B lymphocyte markers in allograft rejection.

    PubMed

    Vallin, Patrice; Désy, Olivier; Béland, Stéphanie; Wagner, Eric; De Serres, Sacha A

    2016-03-01

    The main challenge in solid organ transplantation remains to tackle antibody-mediated rejection. Our understanding of the antibody-mediated response and the capacity to detect it has improved in the last decade. However, the sensitivity and specificity of the current clinical tools to monitor B cell activation are perfectible. New strategies, including the refinement in the characterization of HLA and non-HLA antibodies, as well as a better understanding of the circulating B cell phenotype will hopefully help to non-invasively identify patients at risk or undergoing antibody-mediated allograft damage. The current review discusses the current knowledge of the B cell biomarkers in solid organ transplantation, with a focus on circulating antibodies and peripheral B cells. PMID:26721422

  1. Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1.

    PubMed Central

    Nadeau, K C; Azuma, H; Tilney, N L

    1995-01-01

    Chronic rejection, the most important cause of long-term graft failure, is thought to result from both alloantigen-dependent and -independent factors. To examine these influences, cytokine dynamics were assessed by semiquantitative competitive reverse transcriptase-PCR and by immunohistology in an established rat model of chronic rejection lf renal allografts. Isograft controls develop morphologic and immunohistologic changes that are similar to renal allograft changes, although quantitatively less intense and at a delayed speed; these are thought to occur secondary to antigen-independent events. Sequential cytokine expression was determined throughout the process. During an early reversible allograft rejection episode, both T-cell associated [interleukin (IL) 2, IL-2 receptor, IL-4, and interferon gamma] and macrophage (IL-1 alpha, tumor necrosis factor alpha, and IL-6) products were up-regulated despite transient immunosuppression. RANTES (regulated upon activation, normal T-cell expressed and secreted) peaked at 2 weeks; intercellular adhesion molecule (ICAM-1) was maximally expressed at 6 weeks. Macrophage products such as monocyte chemoattractant protein (MCP-1) increased dramatically (to 10 times), presaging intense peak macrophage infiltration at 16 weeks. In contrast, in isografts, ICAM-1 peaked at 24 weeks. MCP-1 was maximally expressed at 52 weeks, commensurate with a progressive increase in infiltrating macrophages. Cytokine expression in the spleen of allograft and isograft recipients was insignificant. We conclude that chronic rejection of kidney allografts in rats is predominantly a local macrophage-dependent event with intense up-regulation of macrophage products such as MCP-1, IL-6, and inducible nitric oxide synthase. The cytokine expression in isografts emphasizes the contribution of antigen-independent events. The dynamics of RANTES expression between early and late phases of chronic rejection suggest a key role in mediating the events of the

  2. Influence of human leukocyte antigen matching on liver allograft survival and rejection: "the dualistic effect".

    PubMed

    Donaldson, P; Underhill, J; Doherty, D; Hayllar, K; Calne, R; Tan, K C; O'Grady, J; Wight, D; Portmann, B; Williams, R

    1993-06-01

    To date only one published large series of human leukocyte antigen matching and liver allograft survival exists, and considerable confusion has arisen about the advantage or disadvantage of human leukocyte antigen matching. In the present study we have reinvestigated the relationship between human leukocyte antigen mismatch and graft survival in 466 first liver allografts, seeking to clarify the relationship between human leukocyte antigen and both acute rejection and the vanishing bile duct syndrome. In view of current criticism regarding the accuracy of serological tissue typing for human leukocyte antigen-DR, we have used both classic serology and restriction fragment length polymorphism analysis to ensure the accurate assignment of recipient DR types. In addition, we have used polymerase chain reaction amplification and allele-specific and sequence-specific oligonucleotide probes to retest the hypothesis that human leukocyte antigen class II matching may increase susceptibility to the vanishing bile duct syndrome. One-year graft survival was significantly lower in patients with zero or two human leukocyte antigen-A mismatches (52% and 63%, respectively) than in those with one human leukocyte antigen--A mismatch (69%) (p = 0.016 and p = 0.018). A similar effect of B mismatching was observed, with a 1-yr graft survival of 73% for those with one compared with 60% for those with two human leukocyte antigen-B mismatches. In contrast no correlation was found between DR mismatch and graft survival. Human leukocyte antigen class I matching appears to influence graft survival largely through the occurrence of acute rejection and the development of the vanishing bile duct syndrome.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8514248

  3. Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target.

    PubMed

    Welsh, Kerry J; Zhao, Bihong; Buja, L Maximilian; Brown, Robert E

    2016-01-01

    Cardiac allograft rejection remains a problem, despite advances with immunosuppressants. Understanding the mechanisms behind rejection is essential for developing targeted therapies. The goal of this investigation is to explore Sirtuin 1 (Sirt1) as a therapeutic target for cardiac allograft rejection. Thirteen endomyocardial biopsy specimens with acute cellular rejection (grade 2R or 3R) were selected. CD3, CD4, CD8, CD20, CD68, T-cell intracytoplasmic antigen (TIA-1), and Sirt1 expressions were determined by immunohistochemical stains. Comparison of Sirt1 expression was made with 10 cases of grade 0R and grade 1R. Quantitative image analysis was performed. There were 2 cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Sirtuin 1 expression was present in the majority of mononuclear cells (median percentage, 73.5; interquartile range, 51.2-100%); staining was also observed in cardiomyocytes. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, coinciding with acute cellular rejection. Sirtuin 1 expression in the nuclei of FoxP3+ cells can lead to deacetylation and inactivation of FoxP3 rendering the T-suppressor cells inactive and promoting acute cellular rejection. The use of a Sirt1 inhibitor may be a therapeutic option in expanding the functionality of the FoxP3+ T-suppressor cells and moderating the severity of such rejection. PMID:26771391

  4. Anti-huCD20 Antibody Therapy for Antibody-Mediated Rejection of Renal Allografts in a Mouse Model

    PubMed Central

    Abe, Toyofumi; Ishii, Daisuke; Gorbacheva, Victoria; Kohei, Naoki; Tsuda, Hidetoshi; Tanaka, Toshiaki; Dvorina, Nina; Nonomura, Norio; Takahara, Shiro; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

    2016-01-01

    We have reported that B6.CCR5−/− mice reject renal allografts with high serum donor-specific antibody (DSA) titers and marked C4d deposition in grafts, features consistent with AMR. B6.huCD20/CCR5−/− mice, where human CD20 expression is restricted to B cells, rejected A/J renal allografts by day 26 post-transplant with DSA first detected in serum on day 5 post-transplant and increased thereafter. Recipient treatment with anti-huCD20 mAb prior to the transplant and weekly up to 7 weeks post-transplant promoted long-term allograft survival (> 100 days) with low DSA titers. To investigate the effect of B cell depletion at the time serum DSA was first detected, recipients were treated with anti-huCD20 mAb on days 5, 8 and 12 post-transplant. This regimen significantly reduced DSA titers and graft inflammation on day 15 post-transplant and prolonged allograft survival > 60 days. However, DSA returned to the titers observed in control treated recipients by day 30 post-transplant and histological analyses on day 60 post-transplant indicated severe interstitial fibrosis. These results indicate that anti-huCD20 mAb had the greatest effect as a prophylactic treatment and that the distinct kinetics of DSA responses accounts for acute renal allograft failure versus the development of fibrosis. PMID:25731734

  5. Clinical presentation, risk factors and treatment outcomes of first allograft rejection after penetrating keratoplasty in early and late postoperative period

    PubMed Central

    Perera, C; Jhanji, V; Lamoureux, E; Pollock, G; Favilla, I; Vajpayee, R B

    2012-01-01

    Purpose Corneal graft rejection is the most common reason for the failure of an allograft corneal transplant. We undertook this study to identify and compare risk factors and treatment outcomes for early and late corneal graft rejections after optical penetrating keratoplasty. Methods A retrospective case file analysis of 880 primary penetrating keratoplasties was performed at a tertiary ophthalmic care centre. Patients were divided into early rejectors (rejection episode within 6 months postoperatively) and late rejectors (rejection episode after 6 months postoperatively). Main parameters evaluated were demographics, preoperative diagnosis and clinical signs, donor tissue details, surgical technique, details of rejection episode, treatment, and outcome information. Results A total of 156 patients with rejection episodes were identified. Of these, 42 (26.9%) patients experienced early rejection episodes and 114 (73.1%) patients experienced late rejection episodes. Preoperative donor and recipient characteristics, surgical technique, and clinical presentation of graft rejection were found to be similar between both groups after a Bonferroni correction was applied (P>0.005). Treatment outcomes of graft rejections were not significantly different (P=0.46) between early and late rejectors, with 83% of patients responding to rejection treatment (80% early rejectors; 85% late rejectors). Conclusion Patients with early and late graft rejection have similar characteristics and both groups respond to treatment equally. PMID:22344190

  6. Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.

    PubMed

    Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

    2016-06-01

    While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. PMID:27165816

  7. Immunomodulation of vascular endothelium: Effects of ultraviolet B irradiation on vein allograft rejection

    SciTech Connect

    Marin, M.L.; Hardy, M.A.; Gordon, R.E.; Reemtsma, K.; Benvenisty, A.I. )

    1990-01-01

    Prosthetic grafts of vein allografts are inadequate as small-diameter vessel substitutes. We have applied ultraviolet B (UVB) irradiation to modulate the immunogenicity of vein allografts to avoid immunologic injury. The veins of male ACI rats were irradiated with UVB (60 mJ/cm2) in situ and transplanted to male ACI rats (autografts) and female Lewis rats (allografts). Nonirradiated veins served as controls. At 4, 7, 14, and 28 days, all grafts were patent and were studied for morphologic changes by scanning electron microscopy and for immunogold labeling of major histocompatibility complex class II antigen expression. In autografts, scanning electron microscopy demonstrated minimal endothelial loss after grafting, regardless of UVB irradiation. Untreated allografts showed severe endothelial injury 4, 7, and 14 days after transplantation. UVB irradiation of veins protected allografts from injury to the endothelium and basement membrane. Major histocompatibility complex class II-positive endothelial cells were not seen in autografts but were seen in 40% of cells 4 days after transplantation in untreated allografts. UVB-treated allografts showed MHC class II antigen expression labeling of 20% of the endothelial cells. Barr body analysis demonstrated the donor origin of these endothelial cells. UVB irradiation of rat vein allografts prolongs endothelial survival while decreasing endothelial surface expression of class II antigens. These data suggest that modification of vein immunogenicity with UVB irradiation may permit functional survival of small-vessel allografts without chronic immunosuppression.

  8. Combined use of myeloid-related protein 8/14 and procalcitonin as diagnostic markers for acute allograft rejection in kidney transplantation recipients.

    PubMed

    Jung, Da-Yeon; Park, Jae Berm; Lee, Eun-Na; Lee, Hyun-Ah; Joh, Jae-Won; Kwon, Choon Hyuck; Ki, Chang-Seok; Lee, Soo-Youn; Kim, Sung-Joo

    2008-02-01

    The myeloid-related proteins 8 and 14 exist as a dimeric complex (MRP 8/14) and serve as early and highly specific markers for inflammatory processes, such as allograft rejection and non-viral (bacterial or fungal) infections. An elevated procalcitonin (PCT) concentration in serum also serves as a diagnostic indicator of non-viral infection. Therefore, by measuring both MRP 8/14 and PCT serum concentrations, one may be able to distinguish between acute allograft rejection and non-viral infections in non-rejection transplant recipients. Here, we investigated whether MRP 8/14 and PCT can function as prognostic (Study I) or diagnostic (Study II) markers for allograft rejection in renal transplant recipients. In Study I, the serum concentrations of MRP 8/14 and PCT during the first 2 weeks after transplantation did not differ between patients who did and did not suffer organ rejection within 1 year post-transplantation; these findings suggest that the MRP 8/14 and PCT parameters are not valid prognostic markers. However, in Study II, patients with acute rejection or non-rejection/non-viral infection groups displayed a significant increase in serum MRP 8/14 concentration, and non-rejection patients with non-viral infections only had elevation in the PCT serum concentrations. These results indicate that the combined use of MRP 8/14 and PCT serum concentrations can allow one to distinguish between allograft rejection and other inflammatory processes, such as infection. PMID:18158120

  9. Cutting edge: blockade of the CD28/B7 costimulatory pathway inhibits intestinal allograft rejection mediated by CD4+ but not CD8+ T cells.

    PubMed

    Newell, K A; He, G; Guo, Z; Kim, O; Szot, G L; Rulifson, I; Zhou, P; Hart, J; Thistlethwaite, J R; Bluestone, J A

    1999-09-01

    The effect of blocking the CD28/B7 costimulatory pathway on intestinal allograft rejection was examined in mice. Murine CTLA4Ig failed to prevent the rejection of allografts transplanted into wild-type or CD4 knockout (KO) mice but did inhibit allograft rejection by CD8 KO recipients. This effect was associated with decreased intragraft mRNA for IFN-gamma and TNF-alpha and increased mRNA for IL-4 and IL-5. This altered pattern of cytokine production was not observed in allografts from murine CTLA4Ig-treated CD4 KO mice. These data demonstrate that blockade of the CD28/B7 pathway has different effects on intestinal allograft rejection mediated by CD4+ and CD8+ T cells and suggest that these T cell subsets have different costimulatory requirements in vivo. The results also suggest that the inhibition of CD4+ T cell-mediated allograft rejection by CTLA4Ig may be related to down-regulation of Th1 cytokines and/or up-regulation of Th2 cytokines. PMID:10452966

  10. Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction.

    PubMed

    Bombas, A; Stein-Oakley, A N; Baxter, K; Thomson, N M; Jablonski, P

    1999-01-01

    Non-allogeneic factors such as increased nephron "workload" may contribute to chronic renal allograft rejection. Reducing dietary protein from 20% to 8% was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, "tolerised" by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-beta1 mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8% lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage. PMID:10080402

  11. Genetic or Pharmaceutical Blockade of Phosphoinositide 3-Kinase P110δ Prevents Chronic Rejection of Heart Allografts

    PubMed Central

    Rose, Marlene L.; McCormack, Ann M.; Sarathchandra, Padmini; Okkenhaug, Klaus; Marelli-Berg, Federica M.

    2012-01-01

    Chronic rejection is the major cause of long-term heart allograft failure, characterized by tissue infiltration by recipient T cells with indirect allospecificity. Phosphoinositol-3-kinase p110δ is a key mediator of T cell receptor signaling, regulating both T cell activation and migration of primed T cells to non-lymphoid antigen-rich tissue. We investigated the effect of genetic or pharmacologic inactivation of PI3K p110δ on the development of chronic allograft rejection in a murine model in which HY-mismatched male hearts were transplanted into female recipients. We show that suppression of p110δ activity significantly attenuates the development of chronic rejection of heart grafts in the absence of any additional immunosuppressive treatment by impairing the localization of antigen-specific T cells to the grafts, while not inducing specific T cell tolerance. p110δ pharmacologic inactivation is effective when initiated after transplantation. Targeting p110δ activity might be a viable strategy for the treatment of heart chronic rejection in humans. PMID:22479345

  12. Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection.

    PubMed

    Loupy, Alexandre; Lefaucheur, Carmen; Vernerey, Dewi; Chang, Jessica; Hidalgo, Luis G; Beuscart, Thibaut; Verine, Jerome; Aubert, Olivier; Dubleumortier, Sébastien; Duong van Huyen, Jean-Paul; Jouven, Xavier; Glotz, Denis; Legendre, Christophe; Halloran, Philip F

    2014-10-01

    Antibody-mediated rejection (ABMR) is the leading cause of kidney allograft loss. We investigated whether the addition of gene expression measurements to conventional methods could serve as a molecular microscope to identify kidneys with ABMR that are at high risk for failure. We studied 939 consecutive kidney recipients at Necker Hospital (2004-2010; principal cohort) and 321 kidney recipients at Saint Louis Hospital (2006-2010; validation cohort) and assessed patients with ABMR in the first 1 year post-transplant. In addition to conventional features, we assessed microarray-based gene expression in transplant biopsy specimens using relevant molecular measurements: the ABMR Molecular Score and endothelial donor-specific antibody-selective transcript set. The main outcomes were kidney transplant loss and progression to chronic transplant injury. We identified 74 patients with ABMR in the principal cohort and 54 patients with ABMR in the validation cohort. Conventional features independently associated with failure were donor age and humoral histologic score (g+ptc+v+cg+C4d). Adjusting for conventional features, ABMR Molecular Score (hazard ratio [HR], 2.22; 95% confidence interval [95% CI], 1.37 to 3.58; P=0.001) and endothelial donor-specific antibody-selective transcripts (HR, 3.02; 95% CI, 1.00 to 9.16; P<0.05) independently associated with an increased risk of graft loss. The results were replicated in the independent validation group. Adding a gene expression assessment to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 1.01; 95% CI, 0.57 to 1.46; P<0.001; integrated discrimination improvement, 0.16; P<0.001). Compared with conventional assessment, the addition of gene expression measurement in kidney transplants with ABMR improves stratification of patients at high risk for graft loss. PMID:24700874

  13. Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats.

    PubMed

    Ebrahimi, Ammar; Kardar, Gholam Ali; Teimoori-Toolabi, Ladan; Toolabi, LadanTeimoori; Ghanbari, Hossein; Sadroddiny, Esmaeil

    2016-01-15

    Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNγ and TNFα were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects. PMID:26506443

  14. Donor Heart Treatment With COMP-Ang1 Limits Ischemia-Reperfusion Injury and Rejection of Cardiac Allografts.

    PubMed

    Syrjälä, S O; Nykänen, A I; Tuuminen, R; Raissadati, A; Keränen, M A I; Arnaudova, R; Krebs, R; Koh, G Y; Alitalo, K; Lemström, K B

    2015-08-01

    The major cause of death during the first year after heart transplantation is primary graft dysfunction due to preservation and ischemia-reperfusion injury (IRI). Angiopoietin-1 is a Tie2 receptor-binding paracrine growth factor with anti-inflammatory properties and indispensable roles in vascular development and stability. We used a stable variant of angiopoietin-1 (COMP-Ang1) to test whether ex vivo intracoronary treatment with a single dose of COMP-Ang1 in donor Dark Agouti rat heart subjected to 4-h cold ischemia would prevent microvascular dysfunction and inflammatory responses in the fully allogeneic recipient Wistar Furth rat. COMP-Ang1 reduced endothelial cell-cell junction disruption of the donor heart in transmission electron microscopy during 4-h cold ischemia, improved myocardial reflow, and reduced microvascular leakage and cardiomyocyte injury of transplanted allografts during IRI. Concurrently, the treatment reduced expression of danger signals, dendritic cell maturation markers, endothelial cell adhesion molecule VCAM-1 and RhoA/Rho-associated protein kinase activation and the influx of macrophages and neutrophils. Furthermore, COMP-Ang1 treatment provided sustained anti-inflammatory effects during acute rejection and prevented the development of cardiac fibrosis and allograft vasculopathy. These results suggest donor heart treatment with COMP-Ang1 having important clinical implications in the prevention of primary and subsequent long-term injury and dysfunction in cardiac allografts. PMID:25932532

  15. Effect of graft preservation and acute rejection on hypoxia-inducible factor-1 in rat cardiac allografts.

    PubMed

    Keränen, M A I; Nykänen, A I; Krebs, R; Tuuminen, R; Sandelin, H; Koskinen, P K; Lemström, K B

    2006-12-01

    Hypoxia plays an integral part in cardiac transplantation as prolonged graft preservation is an individual risk factor for the development of cardiac allograft vasculopathy (CAV). In this study we characterized the role of hypoxia-inducible factor-1 (HIF-1) during prolonged graft preservation, ischemia-reperfusion (I/R), acute rejection, and chronic rejection. Heart transplantations were performed from Dark Agouti (DA) to Wister-Furth (allo) or DA to DA (syn) rats, without immunosuppression (acute rejection model, harvested at day 5) or with cyclosporine (chronic rejection model, harvested at day 60). To study the effect of preservation on HIF-1 regulation, normal DA hearts were subjected to different cold ischemia times with or without 45 minutes of additional warm ischemia. The role of I/R was studied by harvesting syngrafts at different time points after reperfusion. Real-time reverse-transcriptase polymerase chain reaction quantified total HIF-1 mRNA, while enzyme-linked immunosorbent assay and immunohistochemistry quantified and localized HIF-1 protein. Our results show that HIF-1 nuclear immunoreactivity is increased during graft preservation and I/R leads to loss of nuclear HIF-1 immunoreactivity. Acute rejection induced HIF-1 in mRNA level. Our findings thus indicated that HIF-1 is activated during transplantation and suggested that manipulation of the HIF-1 pathway might reveal new therapeutic options to manage CAV. PMID:17175275

  16. Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts.

    PubMed

    Streblow, D N; Hwee, Y K; Kreklywich, C N; Andoh, T; Denton, M; Smith, P; Hart, E; Broekel, R; Pallett, C; Rogers, K; Streblow, A D; Chuop, M; Perry, A; Slifka, M; Messaoudi, I; Orloff, S L

    2015-07-01

    Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naïve or H2 O2 -inactivated RCMV-vaccinated Lewis recipients. Recipients of RCMV-infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection-POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T-cell and B-cell arms of the adaptive immune response provide protection against CMV-accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti-viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. PMID:25766876

  17. Remote noninvasive allograft rejection monitoring for heart transplant recipients: study protocol for the novel evaluation with home electrocardiogram and remote transmission (NEW HEART) study

    PubMed Central

    2012-01-01

    Background Acute allograft rejection is a major cause of early mortality in the first year after heart transplantation in adults. Although endomyocardial biopsy (EMB) is not a perfect "gold standard" for a correct diagnosis of acute allograft rejection, it is considered the best available test and thus, is the current standard practice. Unfortunately, EMB is an invasive and costly procedure that is not without risk. Recent evidence suggests that acute allograft rejection causes delays in ventricular repolarization and thereby increases the cellular action potential duration resulting in a longer QT interval on the electrocardiogram (ECG). No prospective study to date has investigated whether such increases in the QT interval could provide early detection of acute allograft rejection. Therefore, in the Novel Evaluation With Home Electrocardiogram And Remote Transmission (NEW HEART) study, we plan to investigate the potential benefit of daily home QT interval monitoring to predict acute allograft rejection. Methods/design The NEW HEART study is a prospective, double-blind, multi-center descriptive research study. A sample of 325 adult heart transplant recipients will be recruited within six weeks of transplant from three sites in the United States. Subjects will receive the HeartView™ ECG recorder and its companion Internet Transmitter, which will transmit the subject's ECG to a Core Laboratory. Subjects will be instructed to record and transmit an ECG recording daily for 6 months. An increase in the QTC interval from the previous day of at least 25 ms that persists for 3 consecutive days will be considered abnormal. The number and grade of acute allograft rejection episodes, as well as all-cause mortality, will be collected for one year following transplant surgery. Discussion This study will provide "real world" prospective data to determine the sensitivity and specificity of QTC as an early non invasive marker of cellular rejection in transplant recipients

  18. Diagnostic Performance of Echocardiography for the Detection of Acute Cardiac Allograft Rejection: A Systematic Review and Meta-Analysis

    PubMed Central

    Pan, Xudong; Sun, Lizhong

    2015-01-01

    Objective Many studies have addressed the diagnostic performance of echocardiography to evaluate acute cardiac allograft rejection compared with endomyocardial biopsy. But the existence of heterogeneity limited its clinical application. Thus, we conducted a comprehensive, systematic literature review and meta-analysis for the purpose. Methods Studies prior to September 1, 2014 identified by Medline/PubMed, EMBASE and Cochrance were examined by two independent reviews. We conducted meta-analysis by using Meta-DiSc 1.4 software. An assessment tool of QUADAS-2 was applied to evaluate the risk of bias and applicability of the studies. Results Thirty studies met the inclusion criteria of meta-analysis. The four parameters of pressure half time, isovolumic relaxation time, index of myocardial performance and late diastolic mitral annular motion velocity were included in the meta-analysis, with a pooled diagnostic odds ratio of 10.43, 6.89, 15.95 and 5.68 respectively, and the area under the summary receiver operating characteristic curves value of 0.829, 0.599, 0.871 and 0.685 respectively. Conclusion The meta-analysis and systematic review demonstrate that no single parameter of echocardiography showed a reliable diagnostic performance for acute cardiac allograft rejection. A result of echocardiography for ACAR should be comprehensively considered by physicians in the context of clinical presentations and imaging feature. PMID:25822627

  19. Splenic microenvironment and self recognition as factors in allograft rejection in rats. A study using indium-111-labeled cells

    SciTech Connect

    Pollak, R.; Blanchard, J.M.; Lazda, V.A.

    1986-11-01

    Splenectomy facilitates organ allograft survival in some rat strains, and in weak donor-recipient histoincompatible pairs. We have found using a heart spleen twin graft model, using ACI rats as recipients and Lewis rats as donors, that the transplanted heart will survive in most recipients after delayed host splenectomy. The presence of a viable mass of splenic tissue will allow rejection to proceed only when the transplanted spleen is of host origin, and not when it comes from the donor (i.e., when it is allogeneic). The use of 111In-labeled cells has allowed us to show that lymphocyte traffic and trapping is markedly altered in the transplanted allogeneic spleens, when compared with control transplanted syngeneic spleens. Thus, despite the presence of the splenic ''microenvironment,'' cardiac allograft rejection does not occur in the absence of syngeneic splenic tissue. We conclude that the role of the spleen in the immune response is to facilitate the recognition of self and the acquisition of alloreactivity in weak responder rat strains and donor-recipient pairs.

  20. Abnormal Localization of STK17A in Bile Canaliculi in Liver Allografts: An Early Sign of Chronic Rejection

    PubMed Central

    Aini, Wulamujiang; Tamaki, Keiji; Haga, Hironori; Miyagawa-Hayashino, Aya

    2015-01-01

    The biological significance of STK17A, a serine/threonine kinase, in the liver is not known. We analyzed STK17A expression in HepG2 cells and human liver tissue. Accordingly, we investigated whether STK17A could help in identifying earlier changes during the evolution of chronic rejection (CR) after liver transplantation. RT-PCR and immunofluorescence were used to analyze STK17A expression in HepG2 cells. Antibody microarray was performed using human liver samples from CR and healthy donors. Immunohistochemistry was used to verify the clinical utility of STK17A on sequential biopsies for the subsequent development of CR. A novel short isoform of STK17A was found in HepG2 cells. STK17A was localized in the nuclei and bile canaliculi in HepG2 cells and human livers. Microarray of STK17A revealed its decrease in failed liver allografts by CR. During the evolution of CR, the staining pattern of bile canalicular STK17A gradually changed from diffuse linear to focal intermittent. The focal intermittent staining pattern was observed before the definite diagnosis of CR. In conclusion, the present study was the first to find localization of STK17A in normal bile canaliculi. Abnormal expression and localization of STK17A were associated with CR of liver allografts since the early stage of the rejection process. PMID:26305096

  1. Development of cytotoxic antibodies following renal allograft transplantation is associated with reduced graft survival due to chronic vascular rejection.

    PubMed

    Davenport, A; Younie, M E; Parsons, J E; Klouda, P T

    1994-01-01

    We prospectively followed 64 patients who had had no cytotoxic antibodies prior to first cadaveric renal allograft transplantation for post-transplant antibodies. During a mean follow-up period of 62 months (range 45-92) cytotoxic antibodies developed in 36 patients (56%). Sixteen grafts were lost due to chronic vascular rejection in the group of patients who developed antibodies compared to two in those who remained antibody negative, P < 0.01. Renal function was worse in the antibody-positive group, median serum creatinine 215 mumol/l (131-256) (interquartile range) versus 111 mumol/l (98-127) in the antibody-negative group, P = 0.002, and creatinine clearance 39 ml/min (25-55) versus 90 ml/min (55-104), P < 0.001. There were no significant differences in immunosuppressive protocol, HLA-mismatching, blood transfusion history, the number of acute rejection episodes, mean arterial blood pressure, or proteinuria between the groups. The presence of cytotoxic antibodies predated the classical manifestations of chronic vascular rejection. This suggests that humoral mechanisms may play a role in the development of chronic vascular rejection. PMID:7816298

  2. Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection.

    PubMed

    Jiang, Xinguo; Khan, Mohammad A; Tian, Wen; Beilke, Joshua; Natarajan, Ramesh; Kosek, Jon; Yoder, Mervin C; Semenza, Gregg L; Nicolls, Mark R

    2011-06-01

    Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1α mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2⁺ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2⁺ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection. PMID:21606594

  3. Biodistribution of an anti-interleukin 2 receptor monoclonal antibody in rat recipients of a heart allograft, and its use as a rejection marker in gamma scintigraphy

    SciTech Connect

    Thedrez, P.; Paineau, J.; Jacques, Y.; Chatal, J.F.; Pelegrin, A.; Bouchaud, C.; Soulillou, J.P. )

    1989-09-01

    Anti-interleukin-2 receptor monoclonal antibodies have been shown to prevent allograft rejection. This paper reports on the biodistribution of a mouse MoAb directed at the 55 Kd alpha chain of rat interleukin-2 receptor (IL2-R) during allograft rejection. Only a low percentage (approximately 1%) of intact 125I-labeled MoAb was detected in the rejected graft, and irrelevant control IgG1 was found at a similar level. This suggests that most of the injected intact MoAb bound to graft tissue via its monomorphic Fc segment. In contrast, OX39 F(ab')2 fragments showed a preferential localization in the rejected allograft and did not bind to the LEW-to-LEW syngeneic heart graft. Irrelevant F(ab')2 did not concentrate in the allogeneic graft. Accordingly, F(ab')2 fragments from OX39 or irrelevant MoAb were used for gamma-scintigraphy on allograft recipients together with biodistribution studies. Results show that scintigraphy was able to detect allograft accumulation of 131I OX39 F(ab')2, whereas no imaging was obtained when OX39 F(ab')2 was used in the syngeneic combination or when irrelevant 131-IgG1 F(ab')2 was given to allograft recipients. This method, applied to the clinical situation, could be of interest for detection of early graft rejection episodes by immunoscintigraphy using reagents specific for activation determinants on lymphocyte membranes, such as anti-interleukin-2 receptor MoAb.

  4. The Identification of Novel Potential Injury Mechanisms and Candidate Biomarkers in Renal Allograft Rejection by Quantitative Proteomics*

    PubMed Central

    Sigdel, Tara K.; Salomonis, Nathan; Nicora, Carrie D.; Ryu, Soyoung; He, Jintang; Dinh, Van; Orton, Daniel J.; Moore, Ronald J.; Hsieh, Szu-Chuan; Dai, Hong; Thien-Vu, Minh; Xiao, Wenzhong; Smith, Richard D.; Qian, Wei-Jun; Camp, David G.; Sarwal, Minnie M.

    2014-01-01

    Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a “hub” protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of

  5. Reflectance confocal microscopy as a useful diagnostic tool for monitoring of skin containing vascularized composite allograft rejection: A preliminary study on rats.

    PubMed

    Zor, Fatih; Karagoz, Huseyin; Erdemir, Asli Turgut; Karslioglu, Yildirim; Acikel, Cengiz Han; Kapaj, Rezarta; Guzey, Serbulent; Gurel, Mehmet Salih; Isik, Selcuk; Siemionow, Maria

    2016-02-01

    Vascularized composite allografts can undergo immune-mediated rejection, and skin biopsies are needed for monitoring of the transplant. However it is an invasive method, and requires processing time and pathological assessment. The purpose of this study is to use a new noninvasive monitoring method of the reflectance confocal microscopy (RCM) to determine severity of the allograft rejection on rats. Five groin flap allotransplantation were performed between 10 male Sprague-Dawley rats. Immunosuppressive therapy with cyclosporine A was given to the recipients during 10 days after surgery and was ended at the 10th postoperative days to allow acute transplant rejection. Following cessation of CsA, concomitant RCM evaluation and skin biopsy was performed every other day from each animal until total rejection of the allograft. Complete rejection of the allograft took nearly about 10 days and 4 or 5 RCM evaluation and skin biopsy was performed from each rat during this period. A total of 17 specimens were evaluated. A scoring system was developed based on the RCM findings. Skin biopsies were evaluated according to the Banff 2007 working classification criteria. RCM evaluation revealed epidermal irregularity and collagen destruction, however mild perivascular inflammation and degeneration of the basal epidermal layer were observed in early and late rejection period respectively with histopathologic evaluation. High correlation was found between the RCM scores and histopathologic grading. The RCM may be the useful tool to reduce the need for skin biopsy for monitoring of the skin containing vascularized composite allograft. © 2015 Wiley Periodicals, Inc. Microsurgery 36:144-151, 2016. PMID:25959719

  6. Phosphorylated S6 Kinase and S6 Ribosomal Protein are Diagnostic Markers of Antibody Mediated Rejection in Heart Allografts

    PubMed Central

    Valenzuela, Nicole M.; Lai, Chi; Zhang, Qiuheng; Gjertson, David; Fishbein, Michael C; Kobashigawa, Jon A; Deng, Mario; Reed, Elaine F.

    2014-01-01

    Background Anti-MHC class I alloantibodies have been implicated in the processes of acute and chronic rejection. These antibodies (Ab) bind to endothelial cells (EC) and transduce signals leading to the activation of cell survival and proliferation pathways, including Src, FAK, mTOR, and downstream targets ERK, S6 kinase (S6K) and S6 ribosomal protein (S6RP). We tested the hypothesis that phosphorylation of S6K, S6RP and ERK in capillary endothelium may serve as an adjunct diagnostic tool for antibody mediated rejection (AMR) in heart allografts. Methods Diagnosis of AMR was based on histology or immunoperoxidase staining of paraffin-embedded tissue consistent with 2013 ISHLT criteria. Diagnosis of acute cellular rejection (ACR) was based on ISHLT criteria. Endomyocardial biopsies from 67 heart transplant recipients diagnosed with acute rejection [33 with pAMR, 18 with ACR (15 with grade 1R, 3 with grade >2R), 16 with pAMR+ACR (13 with 1R and 3 with >2R)] and 40 age- and gender-matched recipients without rejection were tested for the presence of phosphorylated forms of ERK, S6RP and S6K by immunohistochemistry. Results Immunostaining of endomyocardial biopsies with evidence of pAMR showed significant increase in expression of p-S6K and p-S6RP in capillary EC compared to controls. A weaker association was observed between pAMR and p-ERK. Conclusions Biopsies diagnosed with pAMR often showed phosphorylation of S6K and S6RP, indicating that staining for p-S6K and p-S6RP is useful for the diagnosis of AMR. Our findings support a role for antibody-mediated HLA signaling in the process of graft injury. PMID:25511749

  7. Existence of circulating anti-endothelial cell antibodies after heart transplantation is associated with post-transplant acute allograft rejection.

    PubMed

    Lehle, Karla; Kroher, Johannes; Kolat, Philipp; von Süßkind-Schwendi, Marietta; Schmid, Christof; Haneya, Assad; Rupprecht, Leopold; Hirt, Stephan

    2016-05-01

    Anti-endothelial cell antibodies (AECA) may be involved in the development of heart allograft rejection. Its detection might be a cheap and noninvasive method to identify high-risk patients. An indirect immunofluorescence method on human umbilical vein endothelial cells was used to investigate the presence of AECAs in 260 pre- and post-transplant serum samples sequentially collected from 34 patients within the first year after heart transplantation (HTX). The presence of AECAs before (23.5 %) and early after HTX (14.7 %) was associated with a significantly increased risk of early acute rejection (75 and 60 %, respectively) compared to 33 % in AECA-negative patients (p = 0.049). Moreover, rejections from AECA-positive patients were more severe (p = 0.057) with a significantly increased incidence of multiple (p = 0.025). The mean number of the sum of rejection episodes was significantly higher in AECA-positive patients (p ≤ 0.05). Patients free of AECAs mainly received mycophenolate mofetil as primary immunosuppression (p = 0.067). Nevertheless, the presence of AECAs did not affect long-term outcome and mortality of HTX patients. Despite a low number of patient samples, the detection of AECAs before and early after HTX could be used as a biomarker for an increased risk of early acute rejection in high-risk patients. This easy method might be a valuable tool to support screening procedures to improve individualized immunosuppressive therapy. PMID:25820657

  8. Relationship between European Mitochondrial Haplogroups and Chronic Renal Allograft Rejection in Patients with Kidney Transplant

    PubMed Central

    JIMÉNEZ-SOUSA, María Angeles; TAMAYO, Eduardo; GUZMÁN-FULGENCIO, María; FERNÁNDEZ-RODRÍGUEZ, Amanda; HEREDIA-RODRIGUEZ, María; GARCÍA-ÁLVAREZ, Mónica; BERMEJO-MARTIN, Jesús F; PINEDA-TENOR, Daniel; RUIZ-GRANADO, Patricia; ALVAREZ-FUENTE, Elisa; GÓMEZ-SANCHEZ, Esther; GÓMEZ-HERRERAS, José I; RESINO, Salvador

    2014-01-01

    Mitochondrial DNA variants may contribute to differences in mitochondrial function, leading to an altered immune system. The aim of this study was to analyze the relationship between mtDNA haplogroups and the development of chronic allograft dysfunction in patients with kidney transplant. A retrospective observational study was carried out on 261 patients who received kidney transplant (114 had stable transplant and 147 patients developed chronic allograft dysfunction). DNA samples were genotyped for 14 mtDNA polymorphisms by using Sequenom's MassARRAY platform (San Diego, CA, USA). Only European white patients within the N macro-cluster were included. Patients with haplogroups V (odds ratio (OR)=0.32; p=0.037) and J (OR=0.36; p=0.038) showed lower odds for developing CRAD than patients with haplogroup H. After adjusting for the most significant variables, haplogroups V and J tended to statistical significance (p=0.091 and p=0.067 respectively). This is a preliminary study in which mtDNA haplogroups seem to be implicated in susceptibility or protection for developing chronic allograft dysfunction. PMID:25170295

  9. Protective function of pirfenidone and everolimus on the development of chronic allograft rejection after experimental lung transplantation.

    PubMed

    von Suesskind-Schwendi, M; Heigel, E; Pfaehler, S; Haneya, A; Schmid, C; Hirt, S W; Lehle, K

    2016-07-01

    Long-term survival of lung allografts is limited by chronic rejection (CR). Oxidative stress (OxS) plays a central role in the development of CR. We investigated the influence of pirfenidone (alone or in combination with everolimus) on OxS and CR. A rat model of left lung allo-transplantation (F344-to-WKY) was used to evaluate the effects of pirfenidone alone [0,85% in chow from postoperative day (POD) -3 to 20/60] and in combination with everolimus [2,5 mg/kg bw daily from POD 7 to 20/60]. Allografts of non-treated animals, everolimus treated animals and right, non-transplanted lungs were used as references. Immunohistology of myeloperoxidase (MPO), haemoxygenase-1 (HO-1), iron and platelet-derived-growth-factor-receptor-alpha (PDGFR-a) were performed. On POD 20, all groups showed severe acute rejection (ISHLT A3-4/B1R-B2R). Groups treated with pirfenidone showed a lower interstitial inflammatory infiltration and a lower participation of highly fibrotic degenerated vessels (ISHLT-D2R). In the long term follow up (POD 60), pirfenidone alone significantly reduced chronic airway rejection (ISHLT-C; p≤0.05), interstitial fibrosis (IF; p≤0.05), content of collagen (p≤0.05), expression of PDGFR-a (p≤0.05) and the deposition of iron (p≤0.05). All groups treated with pirfenidone showed a high expression of the cytoprotective enzyme HO-1 (p≤0.05). The additional application of everolimus resulted in a significant decrease of chronic airway rejection (ISHLT-C; p≤0.05), vasculopathy (ISHLT; p≤0.05) and IF (p≤0.05). In conclusion, early application of pirfenidone inhibited the progression of CR by its anti-fibrotic and anti-oxidative properties. The additional application of an m-TOR-inhibitor increased the anti-fibrotic effects of pirfenidone which resulted in a reduction of CR after experimental LTx. PMID:26707547

  10. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma.

    PubMed

    Spain, L; Higgins, R; Gopalakrishnan, K; Turajlic, S; Gore, M; Larkin, J

    2016-06-01

    Immune checkpoint inhibitors such as ipilimumab and nivolumab improve survival in patients with advanced melanoma and are increasingly available to clinicians for use in the clinic. Their safety in organ transplant recipients is not well defined but published case reports describing treatment with ipilimumab have not been complicated by graft rejection. No cases of anti-programmed cell death protein 1 administration are reported in this group. We describe a case of acute graft rejection in a kidney transplant recipient after treatment with nivolumab, after progression on ipilimumab. Potential factors increasing the risk of graft rejection in this case are discussed, in particular the contribution of nivolumab. PMID:26951628

  11. Severing corneal nerves in one eye induces sympathetic loss of immune privilege and promotes rejection of future corneal allografts placed in either eye.

    PubMed

    Paunicka, K J; Mellon, J; Robertson, D; Petroll, M; Brown, J R; Niederkorn, J Y

    2015-06-01

    Less than 10% of corneal allografts undergo rejection even though HLA matching is not performed. However, second corneal transplants experience a threefold increase in rejection, which is not due to prior sensitization to histocompatibility antigens shared by the first and second transplants since corneal grafts are selected at random without histocompatibility matching. Using a mouse model of penetrating keratoplasty, we found that 50% of the initial corneal transplants survived, yet 100% of the subsequent corneal allografts (unrelated to the first graft) placed in the opposite eye underwent rejection. The severing of corneal nerves that occurs during surgery induced substance P (SP) secretion in both eyes, which disabled T regulatory cells that are required for allograft survival. Administration of an SP antagonist restored immune privilege and promoted graft survival. Thus, corneal surgery produces a sympathetic response that permanently abolishes immune privilege of subsequent corneal allografts, even those placed in the opposite eye and expressing a completely different array of foreign histocompatibility antigens from the first corneal graft. PMID:25872977

  12. Vascularized composite allotransplantation: current standards and novel approaches to prevent acute rejection and chronic allograft deterioration.

    PubMed

    Kueckelhaus, Maximilian; Fischer, Sebastian; Seyda, Midas; Bueno, Ericka M; Aycart, Mario A; Alhefzi, Muayyad; ElKhal, Abdallah; Pomahac, Bohdan; Tullius, Stefan G

    2016-06-01

    The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, >100 upper extremity transplants, 30 face transplants, and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody-mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations toward cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy, and sentinel flaps may enable earlier diagnosis of rejection. Cell-based therapies are being explored to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good midterm results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long-term graft outcomes. PMID:26265179

  13. Long-term efficacy of atorvastatin in allograft rejection following renal transplantation: A randomized clinical trial.

    PubMed

    Amirzargar, Mohammad A; Hosseini, Arsha Tafreshi; Gholiaf, Mahmood; Dadras, Farahnaz; Khoshjoo, Farhad

    2015-09-01

    Statins are a class of drug that can efficiently reduce the level of low-density lipoprotein (LDL) as well as increase the LDL receptors. Several non-lipid-lowering effects of this type of drug have been described. It is reported that they have an influence in preventing graft rejection, especially of the acute type. In this study, patients with end-stage renal disease and candidates for kidney transplantation were divided into two groups. Group A (intervention group) received atorvastatin for two weeks prior to their transplant surgery while group B (control group) received placebo. The lipid profile was tested (triglycerides, cholesterol, LDL) in all patients two weeks before the transplantation. After transplantation, drug use was stopped. We also checked the LDL serum levels in patients with raised lipid levels (LDL >100) every two weeks. After this period, the serum lipid levels were checked monthly up to six months. Hyperlipidemia, when present, was controlled by fibrates. Concerning the rejection episodes, there was no significant difference between the two groups. In group A (13 men and nine women), three (14.3%) cases of rejection were observed whereas four (21.3%) cases of rejection were seen in group B (11 men and 10 women) (P = 0.5). Within group A, five (22.7%) cases of delayed graft function were found while four (19%) similar cases were observed in group B (P = 0.7). There was no statistically significant difference concerning delayed graft function between the two groups. Despite all the mechanisms attributed to the probable anti-rejection properties of statins, we found no significant correlation with the administration of these drugs before transplantation and the protection against graft rejection episodes. PMID:26354567

  14. OKT3 escalating dose regimens provide effective therapy for renal allograft rejection.

    PubMed

    Woodle, E S; Bruce, D S; Josephson, M; Cronin, D; Newell, K A; Millis, J M; Piper, J B; O'Laughlin, R; Thistlethwaite, J R

    1996-08-01

    Dose-response relationships for anti-CD3 monoclonal antibody (mAb) therapy remain undefined, particularly with respect to higher dose ranges. The clinical efficacy and safety of an OKT3 dosing regimen that incorporates higher doses (escalating dose regimens) was examined in a pilot trial. Patients undergoing acute rejection were treated with a 7-d course of OKT3 in which the daily OKT3 dose was escalated during treatment course (daily doses 5, 5, 5, 5, 10, 15, 25 mg). The total amount of OKT3 given was equal to a standard 14-d course (70 mg). A total of 10 primary cadaveric renal transplant recipients were treated, and data analyzed from a median follow up of 5 months (range 3-13 months). Pre-OKT3 immunosuppressive therapy consisted of ATGAM induction therapy (n = 8), and corticosteroid rejection therapy (n = 6, 18.6 +/- 11.4 mg/kg). Median time of first rejection was 32 d (12-48 d) and median time to OKT3 was 33 d (range 15-42 d). Pre-OKT3 histology (by Banff criteria) included: mild ACR (n = 6), moderate ACR (n = 2), AVR (n = 1), ACR and acute transplant glomerulopathy (n = 1). Rejection reversal rate with escalating dose OKT3 was 100%, and each patient experienced a rapid reversal of rejection (i.e. reversal within 14 d initiation of OKT3 therapy). Six recurrent rejection episodes were diagnosed in 5 patients with a median time to recurrent rejection of 30 d following cessation of OKT3 therapy. All recurrent rejection episodes were successfully treated (FK 506 n = 4, corticosteroids n = 1, and OKT3 n = 1). CMV disease was limited to a single episode of CMV viremia in one patient. PTLD was observed in one patient who had coexisting vascular rejection at the time of PTLD diagnosis. Short- and long-term graft function is excellent (pre-rejection baseline creatinine 1.8 +/- 0.4 mg/dl, current creatinine 1.75 +/- 0.4 mg/dl). Monitoring of OKT3 serum levels revealed that patients maintained therapeutic serum levels for an average of 4 d following the last OKT3 dose

  15. POST-TRANSPLANT HYPERGLYCEMIA IS ASSOCIATED WITH INCREASED RISK OF LIVER ALLOGRAFT REJECTION

    PubMed Central

    Wallia, Amisha; Parikh, Neehar D; Molitch, Mark E; Mahler, Eileen; Tian, Lu; Huang, Jie Jenny; Levitsky, Josh

    2010-01-01

    BACKGROUND Intensive glycemic control has been shown to positively impact outcomes in an intensive care setting. Whether this practice is beneficial after liver transplantation (LT) is not known. METHODS A retrospective review of patients undergoing LT from 2/02-07/04 was conducted to analyze the association between peri-operative hyperglycemia and outcomes after LT. Covariates included pre-existing diabetes, mean glucose three months pre-LT, need for insulin drip post-LT, mean total glucose during the post-LT hospitalization, age, gender, type of transplant, and MELD score. Outcomes within one year of LT included rejection, infection, re-hospitalization, prolonged ventilation, and patient/graft survival. RESULTS 113 LT and 31 liver-kidney recipients were included. By multivariate logistic regression adjusting for covariates, the rejection rate was significantly lower for patients with postoperative glucose levels < 200 mg/dL (n=114) vs. > 200 mg/dL (n=30) (OR 0.055, 95%CI [0.0154, 0.200], p<0.001). The need for prolonged ventilation was more common in patients with glucose < 200 vs. > 200 mg/dL (OR 4.30, 95%CI [1.284, 14.388], p=0.018). While other outcomes, infection, re-hospitalization, patient/graft survival, were not different among the glucose control groups, rejection was associated with increased re-hospitalizations and infections. CONCLUSION Our data demonstrate an association between immediate post-transplant glycemic control and the development of subsequent rejection. Prospective trials investigating the effects of perioperative glycemic control on outcomes and morbidity after LT are warranted. PMID:20098286

  16. Interstitial Pneumonitis and the Risk of Chronic Allograft Rejection in Lung Transplant Recipients

    PubMed Central

    Mihalek, Andrew D.; Rosas, Ivan O.; Padera, Robert F.; Fuhlbrigge, Anne L.; Hunninghake, Gary M.; DeMeo, Dawn L.; Camp, Phillip C.

    2013-01-01

    Background: The presence of interstitial pneumonitis (IP) on surveillance lung biopsy specimens in lung transplant recipients is poorly described, and its impact on posttransplant outcomes is not established. The following study assessed the association of posttransplant IP with the development of bronchiolitis obliterans syndrome (BOS). Methods: We examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N = 145). Patients had bronchoscopies with BAL, and transbronchial biopsies performed for surveillance during posttransplant months 1, 3, 6, and 12 as well as when clinically indicated. Patients were given a diagnosis of IP if, in the absence of active infection and organizing pneumonia, they showed evidence of interstitial inflammation and fibrosis on two or more biopsy specimens. Results: IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; P < .0001) and was significantly associated with time to development of BOS (hazard ratio, 3.8; 95% CI, 1.93-7.39; P = .0001) within the first 6 years posttransplant. The presence of IP did not correlate with a significantly higher risk of mortality or time to death. There was no association between the presence of IP and the development of or time to acute rejection. Conclusions: The presence of IP on lung transplant biopsy specimens suggests an increased risk for BOS, which is independent of the presence of acute cellular rejection. PMID:23715594

  17. Inhibitory effect of trichostatin on allograft rejection of corneal transplantation in rats

    PubMed Central

    Maimaitiming, Reziwan; Yang, Xin; Wupuer, Kelala; Ye, Nan; Pan, Zhiqiang

    2015-01-01

    Background: Using a rat penetrating keratoplasty model, this study aims to explore the inhibitory effect of hachimycin on corneal graft rejection, to provide new basis for its clinical application. Materials and methods: Female adult Sprague-Dawley (SD) rats weighing between 220-250 g were used as acceptors and male or female Wistar rats weighing between 220-250 g were used as donors. The rats with a successful keratoplasty were randomly divided into 3 groups with 10 rats in each group. Group A: penetrating keratoplasty group; Group B: penetrating keratoplasty followed by the application of control eye drops containing eye drops matrix dissolved in 20 g/L DMSO and 900 mL/L artificial tear; Group C: penetrating keratoplasty followed by the application of 0.5 g/L hachimycin eye drops. Hachimycin was dissolved in vitamin E to obtain an eye solution with a pH value of 6~7, and stored at 4°C. The local application of hachimycin eye drops started 5 days after the keratoplasty surgery, 5 times per day until the onset of rejection response. At 4 days after the keratoplasty surgery, slit-lamp microscope was used to observe the transplanted cornea once every two days, and a rejection index (RI) of 0-12 was obtained according to the three graft components represented by corneal transparency, edema, and corneal neovascularization. Results: Penetrating keratoplasty was successfully performed on all the 3 groups of rats. Five days after the keratoplasty, both the transparency and the implant edema showed a score of 1-2 degrees in group A and B. Two weeks later, both these two grafts components increased to a score of 2-3 degrees in group A and B, with an active neovascularization. The group C also showed a transparency and implant edema of 1-2 degrees five days after the keratoplasty surgery. However, a transparent implant without edema was observed in group C two weeks after the keratoplasty surgery. In addition, the newly formed blood vessels disappeared and the retina

  18. Gastroesophageal Reflux Disease Is Associated With an Increased Rate of Acute Rejection in Lung Transplant Allografts

    PubMed Central

    Shah, N.S.; Force, S.D.; Mitchell, P.O.; Lin, E.; Lawrence, E.C.; Easley, K.; Qian, J.; Ramirez, A.; Neujahr, D.C.; Gal, A.; Leeper, K.; Pelaez, A.

    2012-01-01

    Purpose Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients. Methods This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded. Results The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004). Conclusion In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation. PMID:20832573

  19. CD3+ CD57+ lymphocytes are not likely to be involved in antigen-specific rejection processes in long-term allograft recipients.

    PubMed Central

    Reipert, B; Scheuch, C; Lukowsky, A; Reinke, P; Fietze, E; Döcke, W D; Staffa, G; Czerlinksi, S; Hetzer, R; Volk, H D

    1992-01-01

    Cytofluorometric investigation of peripheral blood lymphocytes in 380 long-term (greater than 1 year posttransplantation) allograft recipients showed a significant increase in the proportion of CD3+57+ lymphocytes (greater than 20%) in 20% of patients with renal allografts, 66% of patients with cardiac allografts and 44% of patients with liver allografts. Most of these CD3+57+ cells expressed the CD8 antigen and a variable proportion the HLA-DR antigen. A retrospective analysis showed a poorer prognosis for the clinical outcome in those patients with elevated numbers of CD3+57+ cells in peripheral blood. However, CD57+ lymphocytes could rarely be detected in renal infiltrates by immunohistology. Using the Southern blot technique to analyse the T cell receptor rearrangement of separated CD57+ cells, no clonal or oligoclonal expansion of T cell clones could be detected. Nevertheless, there might be a bias towards the use of particular TCR-V beta gene families in at least some patients, as shown by analysis with monoclonal antibodies. In summary, CD57+ T cells are not likely to be directly involved in the rejection process. The data support the idea of a polyclonal and/or superantigen-driven expansion, but not of an antigen-driven expansion of these cells. Images Fig. 3 PMID:1378363

  20. The haemopoietic and immunogenic capacities of living hybrid bone marrow cells tested in tumour allograft rejection.

    PubMed Central

    Kerckhaert, J A; Hofhuis, F M; Willers, J M

    1975-01-01

    In irradiated mice the capacity to reject allogenic tumours can be reconstituted with syngeneic lymphoid cells if the transferred cells are primed with the allogenicantigen. Living semi-allogeneic cells proved to be 30-100-times more acitve as priming antigen than cell membrane fractions. The tumour-suppressive activity of primed lymphoid cells increased in the following order: bone marrow less than Peyer's patches less than thymus less than spleen less than lymph node cells. Even bone marrowcells showed a considerable suppressing activity after priming with live antigen. It was a great advantage that 2 times 10-6 semi-allogeneic bone marrow cells could be used both for the restoration of the haemopoietic system after irradiation and for stimulation of the transferred parental lymphocytes. Priming with large numbers of semi-allogeneic spleen cells abolished the tumour-suppressive activity of the transferred lymphoid cells. This tolerogenic effect disappeared when the priming cells were pretreated with mitomycin. Tolerance could be induced when the cell donors were treated with cyclophosphamide in combination with the living cells. Cell membranes were not effective. PMID:1150311

  1. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection.

    PubMed

    Shi, Guanfang; Field, David J; Ko, Kyung-ae; Ture, Sara; Srivastava, Kalyan; Levy, Scott; Kowalska, M Anna; Poncz, Mortimer; Fowell, Deborah J; Morrell, Craig N

    2014-02-01

    Th cells are the major effector cells in transplant rejection and can be divided into Th1, Th2, Th17, and Treg subsets. Th differentiation is controlled by transcription factor expression, which is driven by positive and negative cytokine and chemokine stimuli at the time of T cell activation. Here we discovered that chemokine platelet factor 4 (PF4) is a negative regulator of Th17 differentiation. PF4-deficient and platelet-deficient mice had exaggerated immune responses to cardiac transplantation, including increased numbers of infiltrating Th17 cells and increased plasma IL-17. Although PF4 has been described as a platelet-specific molecule, we found that activated T cells also express PF4. Furthermore, bone marrow transplantation experiments revealed that T cell-derived PF4 contributes to a restriction in Th17 differentiation. Taken together, the results of this study demonstrate that PF4 is a key regulator of Th cell development that is necessary to limit Th17 differentiation. These data likely will impact our understanding of platelet-dependent regulation of T cell development, which is important in many diseases, in addition to transplantation. PMID:24463452

  2. The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection.

    PubMed

    Sullivan, Lucy C; Westall, Glen P; Widjaja, Jacqueline M L; Mifsud, Nicole A; Nguyen, Thi H O; Meehan, Aislin C; Kotsimbos, Tom C; Brooks, Andrew G

    2015-01-01

    The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation. PMID:26302084

  3. The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection

    PubMed Central

    Sullivan, Lucy C.; Westall, Glen P.; Widjaja, Jacqueline M. L.; Mifsud, Nicole A.; Nguyen, Thi H. O.; Meehan, Aislin C.; Kotsimbos, Tom C.; Brooks, Andrew G.

    2015-01-01

    The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation. PMID:26302084

  4. Study of the association between the donors and recipients angiotensin-converting enzyme insertion/deletion gene polymorphism and the acute renal allograft rejection

    PubMed Central

    Azmandian, Jalal; Mohamadifar, Mohamadamir; Rahmanian-Koshkaki, Sara; Mehdipoor, Mohammad; Nematollahi, Mohamad-Hadi; Saburi, Amin; Mandegary, Ali

    2015-01-01

    Background: Angiotensin converting enzyme (ACE) is involved in various pathophysiological conditions including renal function. ACE levels are under genetic control. Objectives: This study was designed to investigate the association between the donors and recipients ACE-I/D gene polymorphism and risk of acute rejection outcome in renal allograft recipients. Patients and Methods: ACE-I/D polymorphism was determined in 200 donor-recipient pairs who had been referred to Afzalipour hospital in Kerman. ACE-I/D polymorphism was detected using polymerase chain reaction (PCR). Acute rejection (AR) during at least six months post-transplantation was defined as a 20% increase in creatinine level from the postoperative baseline in the absence of other causes of graft dysfunction which responded to antirejection therapy. Results: The observed allele frequencies were II 9.8%, ID 35.6% and DD 44.4% in donors and II 9.8%, ID 35.1% and DD 52.7% in recipients. There were no significant association between ACE genotypes and AR episodes (ORID=0.96 [0.18-5.00] and ORDD: 1.24 [0.25-6.07] for the donors) and (ORID: 0.29 [0.06-1.45] and ORDD: 0.75 [0.19-2.90] for the recipients). Conclusions: It seems that donor and recipient ACE-I/D genotype might not be a risk factor for acute renal allograft rejection. However, due to conflicting results from this and other studies, multicenter collaborative studies with more participants and concomitant evaluation of ACE polymorphism with other polymorphisms in renin–angiotensin system (RAS) are suggested to determine whether ACE genotypes are significant predictors of renal allograft rejection. PMID:26311652

  5. Role of defensins in the pathogenesis of chronic lung allograft rejection

    PubMed Central

    Tiriveedhi, Venkataswarup; Banan, Babak; Deepti, Saini; Nataraju, Angaswamy; Hachem, Ramsey; Trulock, Elbert; Alexander, Patterson G.; Thalachallour, Mohanakumar

    2014-01-01

    Chronic rejection predominantly manifested as bronchiolitis obliterans syndrome (BOS), still remains a major problem affecting long-term outcomes in human lung transplantation (LTx). Donor specific antibodies (DSA) and infiltration of neutrophils in the graft have been associated with the development of BOS. This study determines the role of defensins, produced by neutrophils, and its interaction with α-1-antitrypsin (AAT) towards induction of airway inflammation and fibrosis which are characteristic hallmarks of BOS. Bronchoalveolar lavage (BAL) and serum from LTx recipients, BOS+ (n=28), BOS-(n=26) and normal healthy controls (n=24) were analyzed. Our results show that BOS+ LTx recipients had higher α-defensins (HNP1-3) and β-defensin2 HBD2 concentration in BAL and serum compared to BOS-DSA-recipients and normal controls (p=0.03). BOS+ patients had significantly lower serum AAT along with higher circulating concentration of HNP-AAT complexes in BAL (p=0.05). Stimulation of primary small airway epithelial cells (SAECs) with HNPs induced expression of HBD2, adhesion molecules (ICAM and VCAM), cytokines (IL-6, IL-1β, IL-13, IL-8 and MCP-1) and growth-factor (VEGF and EGF). In contrast, anti-inflammatory cytokine, IL-10 expression decreased 2 fold (p=0.002). HNPs mediated SAEC activation was completely abrogated by AAT. In conclusion, our results demonstrates that neutrophil secretory product, α-defensins, stimulate β-defensin production by SAECs causing upregulation of pro-inflammatory and pro-fibrotic signaling molecules. Hence, chronic stimulation of airway epithelial cells by defensins can lead to inflammation and fibrosis the central events in the development of BOS following LTx. PMID:24380698

  6. Complement Inhibition for Prevention and Treatment of Antibody-Mediated Rejection in Renal Allograft Recipients.

    PubMed

    Jordan, S C; Choi, J; Kahwaji, J; Vo, A

    2016-04-01

    Therapeutic interventions aimed at the human complement system are recognized as potentially important strategies for the treatment of inflammatory and autoimmune diseases because there is often evidence of complement-mediated injury according to pathologic assessments. In addition, there are a large number of potential targets, both soluble and cell bound, that might offer potential for new drug development, but progress in this area has met with significant challenges. Currently, 2 drugs are approved aimed at inhibition of complement activation. The first option is eculizumab (anti-C5), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Eculizumab has also been studied in human transplantation for the treatment and prevention of antibody-mediated rejection (ABMR). Initial data from uncontrolled studies suggested a significant benefit of eculizumab for the prevention of ABMR in highly HLA-sensitized patients, but a subsequent randomized, placebo-controlled trial failed to meet its primary endpoint. Anecdotal data, primarily from case studies, showed benefits in treating complement-mediated ABMR. A second approved complement-inhibiting therapy is C1 esterase inhibitor (C1-INH), which is approved for use in patients with hereditary angioedema, a condition caused by mutations in the gene that codes for C1-INH. A recent placebo-controlled trial of C1-INH for prevention of ABMR in HLA-sensitized patients found that the drug was safe, with evidence for inhibition of systemic complement activation and complement-activating donor-specific antibodies. Other drugs are now under development. PMID:27234741

  7. Acute Liver Allograft Antibody-Mediated Rejection: an inter-institutional study of routine histopathological features

    PubMed Central

    O'Leary, Jacqueline G.; Shiller, S. Michelle; Bellamy, Christopher; Nalesnik, Michael A.; Kaneku, Hugo; Terasaki, Paul I.; Klintmalm, Göran B.; Demetris, Anthony J.

    2015-01-01

    Acute antibody-mediated rejection (AMR) occurs in a minority of sensitized liver transplant recipients. Although histopathologic characteristics have been described, a generalizable scoring system used to trigger a more in-depth analysis is needed to screen for this rare but important finding. Toward this goal, we created a training and validation cohort from 3 high volume liver transplant programs of putative acute AMR and control cases that were evaluated blindly by 4 independent transplant pathologists. The evaluations were performed on H&E sections alone without knowledge of serum DSA results nor C4d stains. Characteristics strongly correlated with acute AMR included portal eosinophilia (OR=4.37, p<0.001), portal vein endothelial cell hypertrophy (OR=2.88, p<0.001), and eosinophilic central venulitis (OR=2.48, p=0.003). These and other characteristics were incorporated into models created from the training cohort alone. The final Acute-AMR (aAMR) score exhibited a strong correlation with acute AMR in the training (OR=2.86, p<0.001) and validation cohort (OR=2.49, p<0.001). SPSS tree classification was used to select 2 cutoffs, one that optimized specificity at a score >1.75 (sensitivity = 34%, specificity = 87%) and a second that optimized sensitivity at a score >1.0 (sensitivity = 81%, specificity = 71%). In conclusion, routine histopathological features of the aAMR score can be used to screen for acute AMR on routine H&E in liver transplant biopsies, a diagnosis that requires substantiation by donor-specific HLA alloantibody testing, C4d staining, and exclusion of other insults. PMID:25045154

  8. Mitomycin C-treated antigen-presenting cells as a tool for control of allograft rejection and autoimmunity: from bench to bedside.

    PubMed

    Terness, Peter; Kleist, Christian; Simon, Helmut; Sandra-Petrescu, Flavius; Ehser, Sandra; Chuang, Jing-Jing; Mohr, Elisabeth; Jiga, Lucian; Greil, Johann; Opelz, Gerhard

    2009-07-01

    Cells have been previously used in experimental models for tolerance induction in organ transplantation and autoimmune diseases. One problem with the therapeutic use of cells is standardization of their preparation. We discuss an immunosuppressive strategy relying on cells irreversibly transformed by a chemotherapeutic drug. Dendritic cells (DCs) of transplant donors pretreated with mitomycin C (MMC) strongly prolonged rat heart allograft survival when injected into recipients before transplantation. Likewise, MMC-DCs loaded with myelin basic protein suppressed autoreactive T cells of MS patients in vitro and prevented experimental autoimmune encephalitis in mice. Comprehensive gene microarray analysis identified genes that possibly make up the suppressive phenotype, comprising glucocorticoid leucine zipper, immunoglobulin-like transcript 3, CD80, CD83, CD86, and apoptotic genes. Based on these findings, a hypothetical model of tolerance induction by MMC-treated DCs is delineated. Finally, we describe the first clinical application of MMC-treated monocyte-enriched donor cells in an attempt to control the rejection of a haploidentical stem cell transplant in a sensitized recipient and discuss the pros and cons of using MMC-treated antigen-presenting cells for tolerance induction. Although many questions remain, MMC-treated cells are a promising clinical tool for controlling allograft rejection and deleterious immune responses in autoimmune diseases. PMID:19393276

  9. mir-155 regulates cardiac allograft rejection by targing the expression of suppressor of cytokine signaling-1 (DOCS1) in dendritic cells

    PubMed Central

    Gao, Yi; Liu, Fang; Zhou, Qiwei; Guo, Meng; Zhang, Mingjian; Guo, Wenyuan; Wang, Liming; Hu, Liping; Hu, Chaozhou; Shi, Yongzhao; Liu, Yushan; Wang, Quanxing

    2014-01-01

    Previously, we observed that mir-155 is induced during dendritic cell (DC) differentiation. We now demon-strated convincing evidence indicating that mir-155 promotes DC maturation and regulates its capacity for antigen presentation and induction of alloreactive T cell activation. Interestingly, the induction of miR-155 expression in DCs is dependent on the TLR4/Myd88/NF-κB signaling. Our mechanistic studies further revealed that SOCS1 is a direct target for mir-155, and by binding to its 3’UTR, mir-155 is likely to affect SOCS1 translation. Suppression of mir-155 expression in DCs significantly attenuated LPS-induced DC maturation along with reduced capability to stimulate allogeneic T cell proliferation. As a result, administration of antagomiR-155 provided protection for cardiac allografts from rejection. Together, our data support that suppression of miR-155 in DCs could be a viable therapeutic strategy for prevention and treatment of allograft rejection in clinical setting of transplantation. PMID:25550988

  10. Clinical Significance of HLA-DQ Antibodies in the Development of Chronic Antibody-Mediated Rejection and Allograft Failure in Kidney Transplant Recipients

    PubMed Central

    Lee, Hyeyoung; Min, Ji Won; Kim, Ji-Il; Moon, In-Sung; Park, Ki-Hyun; Yang, Chul Woo; Chung, Byung Ha; Oh, Eun-Jee

    2016-01-01

    Abstract With the development of the single antigen beads assay, the role of donor specific alloantibody (DSA) against human leukocyte antigens in kidney transplantation (KT) has been highlighted. This study aimed to investigate the clinical significance of DQ-DSA detected at renal allograft biopsy. We evaluated 263 KT recipients who underwent allograft biopsy and DSA detection at the same time. Among them, 155 patients who were nonsensitized before transplantation were selected to investigate the role of de-novo DQ-DSA. Both the total and nonsensitized subgroup was categorized into 4 groups each according to DSA results as: DQ only, DQ + non-DQ, non-DQ, and no DSA. In the total patient group, post-KT DSA was positive in 79 (30.0%) patients and DQ-DSA was most prevalent (64.6%). In the nonsensitized subgroup, de-novo DSAs were detected in 45 (29.0%) patients and DQ-DSA was also most prevalent (73.3%). The DQ only group showed a significantly longer post-KT duration compared to the other groups (P < 0.05). The overall incidence of antibody-mediated rejection (AMR) was 17.9%. B-DSA, DR-DSA, and DQ-DSA were associated with AMR (P < 0.05), but in the analysis for chronic AMR, only DQ-DSA showed significance in both the total and the nonsensitized subgroup (P < 0.05). On comparison of Banff scores among groups, those representing humoral immunity were significantly dominant in all DSA positive groups compared to the no DSA group (P < 0.05), and higher scores of markers representing chronic tissue injury were more frequently detected in the groups with DQ-DSA. The worst postbiopsy survival was seen in the DQ + non-DQ group of the total patient group, and patients with de-novo DQ-DSA showed poorer graft survival in the nonsensitized subgroup compared to the no DSA group (P < 0.05). In the multivariate analysis, de-novo DQ-DSA was the only significant risk factor associated with late allograft failure (P < 0.05). Our study is the first to

  11. Clinical Significance of HLA-DQ Antibodies in the Development of Chronic Antibody-Mediated Rejection and Allograft Failure in Kidney Transplant Recipients.

    PubMed

    Lee, Hyeyoung; Min, Ji Won; Kim, Ji-Il; Moon, In-Sung; Park, Ki-Hyun; Yang, Chul Woo; Chung, Byung Ha; Oh, Eun-Jee

    2016-03-01

    With the development of the single antigen beads assay, the role of donor specific alloantibody (DSA) against human leukocyte antigens in kidney transplantation (KT) has been highlighted. This study aimed to investigate the clinical significance of DQ-DSA detected at renal allograft biopsy. We evaluated 263 KT recipients who underwent allograft biopsy and DSA detection at the same time. Among them, 155 patients who were nonsensitized before transplantation were selected to investigate the role of de-novo DQ-DSA. Both the total and nonsensitized subgroup was categorized into 4 groups each according to DSA results as: DQ only, DQ + non-DQ, non-DQ, and no DSA. In the total patient group, post-KT DSA was positive in 79 (30.0%) patients and DQ-DSA was most prevalent (64.6%). In the nonsensitized subgroup, de-novo DSAs were detected in 45 (29.0%) patients and DQ-DSA was also most prevalent (73.3%). The DQ only group showed a significantly longer post-KT duration compared to the other groups (P < 0.05). The overall incidence of antibody-mediated rejection (AMR) was 17.9%. B-DSA, DR-DSA, and DQ-DSA were associated with AMR (P < 0.05), but in the analysis for chronic AMR, only DQ-DSA showed significance in both the total and the nonsensitized subgroup (P < 0.05). On comparison of Banff scores among groups, those representing humoral immunity were significantly dominant in all DSA positive groups compared to the no DSA group (P < 0.05), and higher scores of markers representing chronic tissue injury were more frequently detected in the groups with DQ-DSA. The worst postbiopsy survival was seen in the DQ + non-DQ group of the total patient group, and patients with de-novo DQ-DSA showed poorer graft survival in the nonsensitized subgroup compared to the no DSA group (P < 0.05). In the multivariate analysis, de-novo DQ-DSA was the only significant risk factor associated with late allograft failure (P < 0.05). Our study is the first to demonstrate

  12. Immune Privilege of Corneal Allografts

    PubMed Central

    Niederkorn, Jerry Y.; Larkin, D. Frank P.

    2013-01-01

    Corneal transplantation has been performed successfully for over 100 years. Normally, HLA typing and systemic immunosuppressive drugs are not utilized, yet 90% of corneal allografts survive. In rodents, corneal allografts representing maximal histoincompatibility enjoy >50% survival even without immunosuppressive drugs. By contrast, other categories of transplants are invariably rejected in such donor/host combinations. The acceptance of corneal allografts compared to other categories of allografts is called immune privilege. The cornea expresses factors that contribute to immune privilege by preventing the induction and expression of immune responses to histocompatibility antigens on the corneal allograft. Among these are soluble and cell membrane molecules that block immune effector elements and also apoptosis of T lymphocytes. However, some conditions rob the corneal allograft of its immune privilege and promote rejection, which remains the leading cause of corneal allograft failure. Recent studies have examined new strategies for restoring immune privilege to such high-risk hosts. PMID:20482389

  13. Association between the presence of anti-HLA antibodies with acute rejection and chronic allograft nephropathy in the first year after kidney transplantation.

    PubMed

    Toresan, R; Manfro, R C; Proença, M C C; Veronese, F J V; Salim, P H; da Silva, D M; Ribeiro, A R; Edelweiss, M I A; Pegas, K L; Jobim, L F J

    2008-04-01

    The clinical relevance of anti-HLA antibodies following kidney transplantation has been a recent focus of research. Patients who present anti-HLA antibodies in the posttransplantation period have shown higher incidences of acute rejection episodes (ARE) and chronic allograft nephropathy (CAN). The objective of this study was to evaluate the presence of anti-HLA antibodies during the first year after kidney transplantation and their association with the occurrence of ARE and CAN. Eighty-eight kidney transplant recipients were evaluated for the presence of IgG anti-HLA antibodies using an enzyme-linked immunosorbent assay (LAT-M and LAT-1240, One Lambda Inc, Calif, United States). Protocol kidney biopsies were performed in consenting patients. ARE and CAN were diagnosed by clinical, laboratory, and histopathological criteria. Anti-HLA antibodies were observed in 20 (22.7%) patients. At 1 year follow-up, 26.1% presented ARE and 51.2% developed CAN. Nine patients (45%) with antibodies developed ARE as opposed to 20.6% without antibodies and 64.7% developed CAN as opposed to 47.8% of those without antibodies. In the histological analysis, the anti-HLA antibodies were associated with Banff IIA ARE (P = .001) and Banff grade II CAN (P = .012). Routine posttransplantation search for antibodies may identify cases at higher risk for acute and chronic rejection, and perhaps help to tailor the immunosuppressive regimen. PMID:18454996

  14. Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study

    PubMed Central

    Valantine, Hannah A.; Penland, Lolita; Luikart, Helen; Strehl, Calvin; Cohen, Garrett; Khush, Kiran K.; Quake, Stephen R.

    2015-01-01

    Background It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. Methods and Findings In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression (correlation with tacrolimus level, r = −0.867, 95% CI −0.968 to −0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several

  15. High frequency of IL-4 producing helper T lymphocytes associated with a reduced incidence of heart allograft rejection.

    PubMed

    Van Hoffen, E; Polen, E; Robertus-Teunissen, M; De Jonge, N; Lahpor, J R; Gmelig-Meyling, F H; De Weger, R A

    2000-01-01

    The reduction in the frequency of rejection episodes several months after heart transplantation (HTX) correlates with the development of donor-specific nonresponsiveness. This is reflected in a reduced frequency of donor-specific cytotoxic T cells (CTL) in the peripheral blood. We investigated whether the reduced CTL frequency and the incidence of rejection episodes coincided with a change in the frequency of either IL-2- or IL-4-producing helper T lymphocytes (HTL). We measured the frequency of HTL before and at several time points after HTX in the blood of ten recipients, using limiting dilution analysis for IL-2 and IL-4. In most patients, HTL frequencies dropped immediately after transplantation, but returned to pre-HTX values later after transplantation. No consistent decrease or increase in frequencies was observed long after HTX. In contrast to IL-2, the HTL frequencies for IL-4 before transplantation were significantly higher in patients without post-HTX rejection episodes requiring treatment than in patients with such episodes. This phenomenon was observed for the in vitro responses towards both donor and third-party cells. In conclusion, relatively high frequencies of IL-4-producing T cells may have a beneficial effect on the outcome of human heart transplantation, because they are associated with a reduced incidence of rejection episodes after transplantation. PMID:11111999

  16. Preferential accumulation of T helper cells but not cytotoxic T cells characterizes benign subclinical rejection of human liver allografts.

    PubMed

    Baumann, Anna K; Schlue, Jerome; Noyan, Fatih; Hardtke-Wolenski, Matthias; Lehner, Frank; Barg-Hock, Hannelore; Klempnauer, Juergen; Manns, Michael P; Taubert, Richard; Jaeckel, Elmar

    2016-07-01

    Subclinical rejection (SCR) is a common event in protocol biopsies after liver transplantation (LT). So far the interpretation of the underlying histological changes and clinical significance is limited. Previous studies were restricted to SCR manifestations within the first weeks after transplantation with limited follow-up. We analyzed clinical data from our prospective protocol biopsy program and found late SCR (at least 3 months after transplantation) to be a common event (41/94 patients). SCR manifested much later than acute cellular rejection (ACR). In the second year after transplantation, the SCR incidence in protocol biopsies reached a plateau of approximately 25% and remained at this level until the latest observed manifestations more than 5 years after transplantation. During a median follow-up of 32 months after SCR, no acute or chronic rejection, relevant graft fibrosis, graft loss, or liver-related death occurred even without specific therapy for SCR. Immunophenotyping of liver biopsies during SCR showed that similar to ACR, the composition of intrahepatic T cells depended on the severity of histological rejection. However, SCR showed a different pattern of infiltrating T cells with a stronger accumulation of CD4(+) cells, an increasing CD4(+) /CD8(+) ratio, and an increasing CD4(+) forkhead box P3 (FOXP3)(+) regulatory T cell (Treg)/CD8(+) ratio, which was not seen in ACR. These intrahepatic T cell patterns were not reflected in the peripheral blood. In conclusion, late SCR after LT has a good clinical prognosis, and it seems safe to leave it untreated. This benign clinical course compared to ACR is associated with intrahepatic T cell infiltration patterns showing less cytotoxic T cells and more CD4(+) FOXP3(+) Tregs. Liver Transplantation 22 943-955 2016 AASLD. PMID:26929119

  17. Clinical validation of an artificial neural network trained to identify acute allograft rejection in liver transplant recipients.

    PubMed

    Hughes, V F; Melvin, D G; Niranjan, M; Alexander, G A; Trull, A K

    2001-06-01

    Artificial neural networks (ANNs) are techniques of nonlinear data modeling that have been studied in a wide variety of medical applications. An ANN was developed to assist in the diagnosis of acute rejection in liver transplant recipients. We investigated the diagnostic accuracy of this ANN on a new data set of patients from the same hospital. In addition, we compared the diagnostic accuracy of the ANN with that of the individual input variables (alanine aminotransferase [ALT] and bilirubin levels and day posttransplantation). Clinical and biochemical data were collected retrospectively for 124 consecutive liver transplantations (117 patients) over the first 3 months after transplantation. Diagnostic accuracy was calculated using receiver operating characteristic (ROC) curve analysis. The ANN differentiated rejection from rejection-free episodes in the new data set over the first 3 months posttransplantation with an area under the ROC curve of 0.902 and sensitivity and specificity of 80.0% and 90.1% at the optimum decision threshold, respectively. The ANN was significantly more specific than ALT or bilirubin level or day posttransplantation at their corresponding optimum decision thresholds (P <.0001). Peak ANN output occurred 1 day earlier than peak values for either ALT or bilirubin (P <.005). The diagnostic accuracy of the ANN was greater than that of any of the individual variables that had been used as inputs. It would be a useful adjunct to conventional liver function tests for monitoring liver transplant recipients in the early postoperative period. PMID:11443576

  18. Immuno-histological assessment of sub-clinical acute and borderline rejection in renal allograft recipients: Data from a transplant center in India.

    PubMed

    Badwal, Sonia; Kumar, Arun; Hooda, A K; Varma, P P

    2015-11-01

    This single-center study was carried out on living related and unrelated renal transplant recipients (RTRs) to evaluate the usefulness of surveillance biopsies in monitoring stable renal allografts using immuno-histological markers for immune-activation. This is a prospective, longitudinal study. Protocol biopsies of 60 RTRs with stable graft function were evaluated at three, six and 12 months post-transplant. Immuno-histological evaluation was carried out using immune-activation markers (perforins, granzyme and interleukin-2R), phenotypic markers (CD-3 and CD-20), viral markers and C4d. The demographic and clinical profile was recorded for each patient. All cases of acute sub-clinical rejection (SCR) were treated and borderline SCR cases were followed-up without treatment. SCR at three and six months post-transplant was evident in 16.7% and 3.7% of RTRs, respectively. Positive statistical association of SCR was seen with HLA-DR mismatches, whereas patients receiving induction therapy and tacrolimus-based immunosuppression exhibited a lower incidence of SCR. T cell phenotype with persistent expression of immune-activation markers exhibited positive statistical association with interstitial fibrosis and tubular atrophy at 12-month follow-up biopsy. The mean creatinine levels were significantly lower in the protocol biopsy group than the non-protocol biopsy group. No significant difference was found between the mean creatinine levels of the SCR group after treatment and the non-SCR cases within the protocol biopsy group. Early treatment of sub-clinical acute rejection leads to better functional outcomes. However, persistent immune-activation is associated with chronicity and may have implications on long-term graft survival. PMID:26586064

  19. Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection

    SciTech Connect

    Ely, Lauren K.; Green, Katherine J.; Beddoe, Travis; Clements, Craig S.; Miles, John J.; Bottomley, Stephen P.; Zernich, Danielle; Kjer-Nielsen, Lars; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R.

    2010-06-30

    Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801{sup +} individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801{sup FLRGRAYGL}. Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 {micro}M, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

  20. Characteristics of Circulating Donor-Specific Anti-HLA Antibodies and Acute Rejection in the Kidney Allograft

    PubMed Central

    Kannabhiran, Dinesh; Lee, John; Schwartz, Joseph E.; Friedlander, Rex; Aull, Meredith; Muthukumar, Thangamani; Campbell, Sean; Epstein, David; Seshan, Surya V.; Kapur, Sandip; Sharma, Vijay K.; Suthanthiran, Manikkam; Dadhania, Darshana

    2016-01-01

    Background Characteristics of pretransplant antibodies directed at donor HLA (DSA) associated with adverse outcomes in kidney transplant recipients are being elucidated but uncertainties exist. Methods Prospectively screening of pretransplant sera from 543 kidney recipients using single antigen bead assays identified 154 recipients with DSA and 389 without. We investigated the association of DSA features to acute rejection (AR) and graft failure. Results One-year AR incidence was higher in DSA positive group (P<0.001), primarily due to antibody mediated rejection (AMR, 13% vs. 1.8%, P<0.001) and not T-cell mediated rejection (ACR, 5% vs.6%, P=0.65). Risk of AMR increased progressively with a rise in DSA MFI-Sum (P<0.0001). Both DSA MFI-Sum ≥6000 (OR=18; 95%CI, 7.0 to 47; P<0.001) and DSA specificity, presence of DSA against both HLA class I and II (OR=39; 95%CI, 14 to 106; P<0.0001), predicted one-year AMR, independent of other covariates. In a combined model, DSA specificity predicted AMR, independent of DSA MFI-Sum. In multivariable Cox proportional hazards models, the covariate-adjusted hazard ratio for graft failure was 2.03 (95%CI, 1.05 to 3.92; P=0.04) for DSA MFI-Sum≥6000 and 2.23 (95% CI, 1.04 to 4.80; P=0.04) for class I and II DSA. Prediction of graft loss was not independent of AMR. Conclusions Our study supports the hypothesis that characterization of pretransplant DSA, specifically presence of DSA against both HLA class I and II and the strength, as quantified by DSA MFI-Sum, is useful to estimate AMR and graft failure risk in kidney graft recipients. Elevated risk of graft failure is attributable to increased risk of AMR. PMID:25629531

  1. Delayed Cytotoxic T Lymphocyte-Associated Protein 4-Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection.

    PubMed

    Young, J S; Chen, J; Miller, M L; Vu, V; Tian, C; Moon, J J; Alegre, M-L; Sciammas, R; Chong, A S

    2016-08-01

    Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4(+) and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established. PMID:26928966

  2. Prediction of Renal Allograft Acute Rejection Using a Novel Non-Invasive Model Based on Acoustic Radiation Force Impulse.

    PubMed

    Yang, Cheng; Jin, Yunjie; Wu, Shengdi; Li, Long; Hu, Mushuang; Xu, Ming; Rong, Ruiming; Zhu, Tongyu; He, Wanyuan

    2016-09-01

    Point shear wave elastography based on acoustic radiation force impulse is a novel technology used to quantify tissue stiffness by measuring shear wave speed. A total of 115 kidney transplantation recipients were consecutively enrolled in this prospective study. The patients were subdivided into two groups using 1 mo post-transplantation as the cutoff time for determining the development of acute rejection (AR). Shear wave speed was significantly higher in the AR group than in the non-AR group. We created a model called SEV, comprising shear wave speed, estimated glomerular filtration rate and kidney volume change, that could successfully discriminate patients with or without AR. The area under the receiver operating characteristic curve of SEV was 0.89, which was higher than values for other variables; it was even better in patients within 1 mo post-transplantation (0.954), but was lower than the estimated glomerular filtration rate in patients after 1 mo post-transplantation. Therefore, the SEV model may predict AR after renal transplantation with a high degree of accuracy, and it may be more useful in the early post-operative stage after renal transplantation. PMID:27267289

  3. An In vitro reaction between lymphoid cells and target fibroblastic cells: A possible model for in vivo rejection of haemopoietic allografts*

    PubMed Central

    Mayhew, Eric; Bennett, Michael

    1971-01-01

    An in vitro reaction between mouse lymphoid cells and target fibroblastic cells in wells of microtest plates is described, which appears to simulate the in vivo rejection of haemopoietic allografts. Lymphoid cells from non-immunized mice were incubated with L929 or skeletal muscle fibroblasts, the latter from mouse embryos, in 0.02 ml volumes for 18–24 hours. Cell detachment was the measure of cytotoxicity, as the remaining adherent fibroblastic cells were enumerated in plates stained with Giemsa's stain. Cytotoxicity was related to the ratio of lymphoid cells to target cells plated (250:1 was the minimal ratio resulting in consistent cell damage) and to the length of time the two cell populations were incubated together. Neither extrinsic complement nor phytohaemagglutinin was necessary for the response. The lymphoid cells remained cytotoxic following exposure to 1000 R of X-radiation and were only slightly inhibited by rabbit antimouse thymocyte serum. Lymphoid cells from suckling mice were less effective than those from adults. Cyclophosphamide treatment suppressed the function and/or numbers of effective lymphoid cells. Differentiation of competent lymphoid cells from transplanted marrow stem cells was not inhibited by previous thymectomy of the recipient mice. Lymphoid cells were not cytotoxic for syngeneic target cells and were cytotoxic for allogeneic target cells. (C3H/He × C57BL/10Cz) F1 lymphoid cells were effective against C57BL/10Cz, but not C3H/He, target fibroblastic cells, demonstrating immunogenetic specific `hybrid resistance'. ImagesFIG. 1FIG. 6 PMID:4934136

  4. Uptake of donor lymphocytes treated with 8-methoxypsoralen and ultraviolet A light by recipient dendritic cells induces CD4{sup +}CD25{sup +}Foxp3{sup +} regulatory T cells and down-regulates cardiac allograft rejection

    SciTech Connect

    Zheng, De-Hua; Dou, Li-Ping; Wei, Yu-Xiang; Du, Guo-Sheng; Zou, Yi-Ping; Song, Ji-Yong; Zhu, Zhi-Dong; Cai, Ming; Qian, Ye-Yong; Shi, Bing-Yi

    2010-05-14

    Extracorporeal photopheresis (ECP) is an effective immunomodulatory therapy and has been demonstrated to be beneficial for graft-vs-host disease and solid-organ allograft rejection. ECP involves reinfusion of a patient's autologous peripheral blood leukocytes treated ex vivo with 8-methoxypsoralen and UVA light radiation (PUVA). Previous studies focused only on ECP treatment of recipient immune cells. Our study is the first to extend the target of ECP treatment to donor immune cells. The results of in vitro co-culture experiments demonstrate uptake of donor PUVA-treated splenic lymphocytes (PUVA-SPs) by recipient immature dendritic cells (DCs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient DCs. In the same co-culture system, donor PUVA-SPs enhanced production of interleukin-10 and interferon-{gamma} by recipient DCs and impaired the subsequent capability of recipient DCs to stimulate recipient naive T cells. Phagocytosis of donor PUVA-SP (PUVA-SP DCs) by recipient DCs shifted T-cell responses in favor of T helper 2 cells. Infusion of PUVA-SP DCs inhibited cardiac allograft rejection in an antigen-specific manner and induced CD4{sup +}CD25{sup high}Foxp3{sup +} regulatory T cells. In conclusion, PUVA-SP DCs simultaneously deliver the donor antigen and the regulatory signal to the transplant recipient, and thus can be used to develop a novel DC vaccine for negative immune regulation and immune tolerance induction.

  5. Radionuclide surveillance of the allografted pancreas

    SciTech Connect

    George, E.A.; Salimi, Z.; Carney, K.; Castaneda, M.; Garvin, P.J.

    1988-04-01

    To determine the value of scintigraphy to detect posttransplantation complications of the allografted pancreas, we retrospectively reviewed 209 scintigrams obtained with /sup 99m/Tc-sulfur colloid (/sup 99m/Tc-SC) and /sup 99m/Tc-glucoheptonate (/sup 99m/Tc-GH). The scintigraphic studies were performed in 37 recipients of simultaneous renal and pancreatic allografts harvested from the same donor. /sup 99m/Tc-SC was used as an indicator of thrombotic vasculitis; pancreatic perfusion and blood-pool parameters were monitored with /sup 99m/Tc-GH. In 11 of the 37 recipients, scintigraphic abnormalities suggested posttransplantation infarction. Recurrent episodes of acute rejection of the pancreatic allograft, which always coincided with acute rejection of the renal allograft, were monitored in 24 recipients. Rejection-induced ischemic pancreatitis was suggested in 12 of the 24 recipients and persisted in 10 recipients for several weeks after improvement of renal allograft rejection. Pancreatic atrophy was suggested scintigraphically in 16 of the 24 recipients with recurrent episodes of rejection. Spontaneous pancreatic-duct obstruction and obstructive pancreatitis were associated with a scintigraphic pattern similar to that of rejection-induced ischemic pancreatitis. We concluded that the specific radionuclides used in this series are useful for the surveillance and assessment of posttransplantation pancreatic infarction, acute rejection, pancreatitis, and atrophy

  6. Use of local allograft irradiation following renal transplantation

    SciTech Connect

    Halperin, E.C.; Delmonico, F.L.; Nelson, P.W.; Shipley, W.U.; Cosimi, A.B.

    1984-07-01

    Over a 10 year period, 67 recipients of 71 renal allografts received graft irradiation following the diagnosis of rejection. The majority of kidneys were treated with a total dose of 600 rad, 150 rad per fraction, in 4 daily fractions. Fifty-three kidneys were irradiated following the failure of standard systemic immunosuppression and maximally tolerated antirejection measures to reverse an episode of acute rejection. Twenty-two (42%) of these allografts were noted to have stable (i.e. no deterioration) or improved function 1 month following the treatment with irradiation. Eleven (21%) of these allografts maintained function 1 year following transplantation. Biopsies were obtained of 41 allografts. Of the 24 renal allografts with predominantly cellular rejection, 10 (42%) had the process reversed or stabilized at 1 month following irradiation. Five (21%) of these allografts were functioning at 1 year following irradiation. Rejection was reversed or stabilized in 6 of 17 (35%) allografts at 1 month when the histologic features of renal biopsy suggested predominantly vascular rejection. Local graft irradiation has helped maintain a limited number of allografts in patients whose rejection has failed to respond to systemic immunosuppression. Irradiation may also benefit patients with ongoing rejection in whom further systemic immunosuppression is contra-indicated.

  7. Smooth muscle cells of the coronary arterial tunica media express tumor necrosis factor-alpha and proliferate during acute rejection of rabbit cardiac allografts.

    PubMed Central

    Tanaka, H.; Swanson, S. J.; Sukhova, G.; Schoen, F. J.; Libby, P.

    1995-01-01

    Graft coronary arteriosclerosis (GCA) frequently limits the long-term success of cardiac transplantation. The pathogenic mechanisms of and stimuli that provoke GCA remain uncertain. Whatever the initiating factors, deranged control of smooth muscle cells (SMC) proliferation likely contributes to the intimal hyperplasia that produces obstructive lesions. To identify mediators that may contribute to ongoing modulation of SMC functions during acute rejection and to explore the mechanisms of the pathogenesis of graft coronary arteriosclerosis, we studied the kinetics of proliferation and the expression of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory and SMC growth-promoting cytokine, in coronary arterial SMCs in rabbit hearts transplanted heterotopically without immunosuppression. Hearts were harvested at 2 (n = 5), 5 (n = 5), and 8.2 +/- 0.4 (mean +/- SD, n = 5) days after transplantation, just before graft failure as judged clinically. SMC proliferation was assessed by continuous bromodeoxyuridine labeling (BrdU 10 mg/kg/d. s.q.). Whole heart cross sections were stained immunohistochemically with monoclonal antibodies that recognize TNF-alpha, BrdU, and SMCs (muscle alpha-actin). Major epicardial coronary arteries (five to nine profiles in each animal) were evaluated. Histological rejection grades by the International Society for Heart and Lung Transplantation scale at 2, 5, and 10 days were 1.6 +/- 0.9, 2.8 +/- 1.1, and 4.0 +/- 0.0, respectively. Medial SMCs in normal hearts and 2 days after transplant expressed little or no TNF-alpha and displayed negligible BrdU incorporation. At 5 days after transplantation, some medial SMCs stained for TNF-alpha and had a low BrdU labeling index (0.5 +/- 0.8%). At 8.2 days after transplant, almost all medial SMCs expressed TNF-alpha intensely and had a high labeling index (29.8 +/- 8.0%). These results demonstrate that acute rejection activates medial SMCs in coronary arteries to express TNF-alpha and that SMC

  8. Immune mechanisms in organ allograft rejection. V. Pivotal role of the cytotoxic-suppressor T cell subset in the rejection of heart grafts bearing isolated class I disparities in the inbred rat

    SciTech Connect

    Lowry, R.P.; Forbes, R.D.; Blackburn, J.H.; Marghesco, D.M.

    1985-11-01

    The cellular requirements for rejection of heart grafts bearing isolated major histocompatibility complex (MHC) subregion RT1A-encoded class I disparities was assessed by adoptive transfer. Sublethally irradiated (780 rads) (PVG X WF)F1 recipients of irradiated PVG-RT1r1 heart grafts were selectively reconstituted with spleen cells from syngeneic donors previously sensitized with two sequential PVG-RT1r1 skin grafts. PVG-RT1r1 heart grafts were rejected acutely in recipients reconstituted with 10 X 10(6) unfractionated immune spleen cells or inocula (5 X 10(6) cells) depleted of SIg+ cells, but additional depletion of cytotoxic T cells and their precursors resulted in marked prolongation of graft survival. Reducing the reconstituting inocula from 4 X 10(6) to 2.5 X 10(6) spleen cells prolonged graft survival to that observed in unreconstituted recipients. Additional studies were performed to define the immunologic basis for prolonged survival of PVG-RT1r1 heart grafts in homozygous PVG recipients. Although lymphoid cells of naive PVG failed to proliferate on coculture with irradiated PVG-RT1r1, bulk cultures yielding but weak and variable CTL generation, lymphoid cells from specifically sensitized PVG proliferated and generated greater cytotoxic T lymphocyte (CTL) activity under identical conditions, strongly suggesting, therefore, that prolonged heart graft survival in this strain combination is related to low CTL precursor frequency.

  9. Infectious Triggers of Chronic Lung Allograft Dysfunction.

    PubMed

    Gregson, Aric L

    2016-07-01

    Survival after lung transplantation is limited in large part due to the high incidence of chronic rejection, known as chronic lung allograft dysfunction (CLAD). Pulmonary infections are a frequent complication in lung transplant recipients, due both to immunosuppressive medications and constant exposure of the lung allograft to the external environment via the airways. Infection is a recognized risk factor for the development of CLAD, and both acute infection and chronic lung allograft colonization with microorganisms increase the risk for CLAD. Acute infection by community acquired respiratory viruses, and the bacteria Pseudomonas aeruginosa and Staphylococcus aureus are increasingly recognized as important risk factors for CLAD. Colonization by the fungus Aspergillus may also augment the risk of CLAD. Fostering this transition from healthy lung to CLAD in each of these infectious episodes is the persistence of an inflammatory lung allograft environment. PMID:27221821

  10. Preserved saphenous vein allografts for vascular access.

    PubMed

    Piccone, V A; Sika, J; Ahmed, N; LeVeen, H H; DiScala, V

    1978-09-01

    Preserved venous allografts were used as an alternate access procedure in 70 patients receiving dialysis during a three year period. The clinical experience with allograft fistulas revealed an extremely high initial patency rate; absence of infection postoperatively and during three years of dialysis; suitability for dialysis a week after implantation, thus greatly obviating the need for Silastic shunts; a low long term thrombosis rate and the weakly antigenic allograft veins produced no accelerated rejection of subsequently transplanted kidneys. Surviving patients average 172 dialysis treatments per allograft. Allograft fistulas constituted 45 per cent of the last 100 vascular procedures, an indication of the extent of usage. Microscopic examination of grafts retrieved from patients who died during the late follow-up period demonstrated that structural components of the wall of the vein were still identifiable. Allograft venous fistulas offer dependable, safe vascular access, especially in the infection prone patient with diabetes who is receiving dialysis treatment. The clinical results of allograft fistulas suggests a major role for this technique in vascular access operations. PMID:684591

  11. Risk factors of cardiac allograft vasculopathy

    PubMed Central

    Szczurek, Wioletta; Gąsior, Mariusz; Zembala, Marian

    2015-01-01

    Despite advances in prevention and treatment of heart transplant rejection, development of cardiac allograft vasculopathy (CAV) remains the leading factor limiting long-term survival of the graft. Cardiac allograft vasculopathy etiopathogenesis is not fully understood, but a significant role is attributed to endothelial cell damage, caused by immunological and non-immunological mechanisms. Immunological factors include the differences between the recipient's and the donor's HLA systems, the presence of alloreactive antibodies and episodes of acute rejection. Among the non-immunological factors the most important are the age of the donor, ischemia-reperfusion injury and cytomegalovirus infection. The classical cardiovascular risk factors (diabetes, hypertension, obesity and hyperlipidemia) are also important. This study presents an up-to-date overview of current knowledge on the vasculopathy etiopathogenesis and the role played by endothelium and inflammatory processes in CAV, and it also investigates the factors which may serve as risk markers of cardiac allograft vasculopathy. PMID:26855649

  12. Antibody-Mediated Lung Transplant Rejection

    PubMed Central

    Hachem, Ramsey

    2012-01-01

    Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation. PMID:23002428

  13. Cellular and Functional Imaging of Cardiac Transplant Rejection

    PubMed Central

    Wu, Yijen L.; Ye, Qing

    2011-01-01

    Heart transplantation is now an established treatment for patients suffering from end-stage heart diseases. With the advances in immunosuppressive treatment, the survival rate for transplant patients has improved greatly. However, allograft rejection, both acute and chronic, after heart transplantation is still a limitation leading to morbidity and mortality. The current clinical gold standard for screening rejection is endomyocardial biopsy (EMB), which is not only invasive, but also error-prone, due to the limited sample size and the site location of sampling. It would be highly desirable to have reliable and noninvasive alternatives for EMB in monitoring cardiac allograft rejection. The objective of this review is to highlight how cardiovascular imaging can contribute to noninvasively detecting and to evaluating both acute and chronic allograft rejection after heart transplantation, in particular, cardiovascular MRI (CMRI); and how CMRI can assess both immune cell infiltration at the rejecting organ, and the cardiac dysfunctions resulting from allograft rejection. PMID:21359095

  14. Cytokines in immunity and allograft rejection.

    PubMed

    Benjamin, Louis C; Allan, James S; Madsen, Joren C

    2002-01-01

    Cytokines are highly potent regulatory molecules that are secreted by a variety of cells into the local microenvironment. These chemical messengers participate in the activation and regulation of immune function by a variety of mechanisms, including the stimulation and inhibition of cellular proliferation and differentiation. Cytokines also may have chemotactic activity. Six cytokine receptor families have been described, on the basis of their conserved structural features. Many cytokines are classified as proinflammatory cytokines, which promote both innate and adaptive immune responses. Solid-organ transplantation presents several unique challenges to the immune system, and cytokines play an important role in both antigen-dependent and antigen-independent immune recognition. The selective blockade of cytokine-mediated immune responses is a cornerstone of modern immunosuppressive therapy. PMID:12678428

  15. Recipient-derived EDA fibronectin promotes cardiac allograft fibrosis.

    PubMed

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2012-03-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA(-/-)) and wild-type (WT) mice. While EDA(-/-) mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA(-/-) mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which enhance

  16. Targeting Sirtuin-1 prolongs murine renal allograft survival and function.

    PubMed

    Levine, Matthew H; Wang, Zhonglin; Xiao, Haiyan; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R; Hancock, Wayne W; Beier, Ulf H

    2016-05-01

    Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3(+) T-regulatory cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3(+) T-regulatory suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1(fl/fl)CD4(cre)) or mice treated with a Sirtuin-1-specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1(fl/fl)CD4(cre) recipients showed markedly longer survival and improved kidney function. Sirt1(fl/fl)CD4(cre) recipients exhibited donor-specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell-mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration. PMID:27083279

  17. Early right coronary vasospasm presenting with malignant arrhythmias in a heart transplantation recipient without allograft vasculopathy.

    PubMed

    Pistono, M; Brentana, L; Gnemmi, M; Imparato, A; Temporelli, P L; Zingarelli, E; Patané, F; Giannuzzi, P

    2009-01-24

    In heart transplant recipients, the aetiology of coronary vasospasm is largely unknown but it has been reported to be related to coronary vasculopathy or allograft rejection. We report a case of acute, reversible coronary vasospasm which caused malignant arrhythmias in a cardiac transplant recipient one month after transplantation without evidence of coronary vasculopathy or allograft rejection. The patient had a normal post-operative course with no other complications; this case supports the hypothesis that coronary vasospasm is not necessarily related to epicardial coronary artery disease or allograft rejection, but rather may be due to an abnormal reversible vasoreactivity. PMID:17950482

  18. Acute and Chronic Allograft Dysfunction in Kidney Transplant Recipients.

    PubMed

    Goldberg, Ryan J; Weng, Francis L; Kandula, Praveen

    2016-05-01

    Allograft dysfunction after a kidney transplant is often clinically asymptomatic and is usually detected as an increase in serum creatinine level with corresponding decrease in glomerular filtration rate. The diagnostic evaluation may include blood tests, urinalysis, transplant ultrasonography, radionuclide imaging, and allograft biopsy. Whether it occurs early or later after transplant, allograft dysfunction requires prompt evaluation to determine its cause and subsequent management. Acute rejection, medication toxicity from calcineurin inhibitors, and BK virus nephropathy can occur early or later. Other later causes include transplant glomerulopathy, recurrent glomerulonephritis, and renal artery stenosis. PMID:27095641

  19. The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation.

    PubMed

    Martin-Gandul, C; Mueller, N J; Pascual, M; Manuel, O

    2015-12-01

    Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community-acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction. PMID:26474168

  20. Extracorporeal photopheresis in heart transplant rejection.

    PubMed

    Patel, Jignesh; Klapper, Ellen; Shafi, Hedyeh; Kobashigawa, Jon A

    2015-04-01

    Up to 25% of heart transplant recipients develop rejection requiring intervention. While the majority respond to augmentation of immunomodulatory drug therapy, a subset of patients will remain refractory. Extracorporeal photopheresis (ECP) appears particularly useful in the management of select heart transplant recipients at risk of rejection, with recurrent rejection, or rejection associated with hemodynamic compromise. This chapter summarizes the current clinical experience of ECP in heart transplantation. ECP appears to favorably affect both the cellular and humoral arms of the immune response to the allograft and promote a tolerogenic profile. These immunomodulatory effects also appear to decrease development of cardiac allograft vasculopathy. ECP is generally well tolerated with few adverse effects and low infection risk. PMID:25748232

  1. Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.; Smit, B.; Louw, G.; Zuurmond, T.; Els, D.; Du Toit, L.B.; Weideman, A.; Davids, H.; van der Merwe, E.

    1987-09-01

    The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

  2. Recipient–derived EDA fibronectin promotes cardiac allograft fibrosis

    PubMed Central

    Booth, Adam J; Wood, Sherri C; Cornett, Ashley M; Dreffs, Alyssa A; Lu, Guanyi; Muro, Andrés F; White, Eric S; Bishop, D Keith

    2014-01-01

    Advances in donor matching and immunosuppressive therapies have decreased the prevalence of acute rejection of cardiac grafts; however, chronic rejection remains a significant obstacle for long-term allograft survival. While initiating elements of anti-allograft immune responses have been identified, the linkage between these factors and the ultimate development of cardiac fibrosis is not well understood. Tissue fibrosis resembles an exaggerated wound healing response, in which extracellular matrix (ECM) molecules are central. One such ECM molecule is an alternatively spliced isoform of the ubiquitous glycoprotein fibronectin (FN), termed extra domain A-containing cellular fibronectin (EDA cFN). EDA cFN is instrumental in fibrogenesis; thus, we hypothesized that it might also regulate fibrotic remodelling associated with chronic rejection. We compared the development of acute and chronic cardiac allograft rejection in EDA cFN-deficient (EDA−/−) and wild-type (WT) mice. While EDA−/− mice developed acute cardiac rejection in a manner indistinguishable from WT controls, cardiac allografts in EDA−/− mice were protected from fibrosis associated with chronic rejection. Decreased fibrosis was not associated with differences in cardiomyocyte hypertrophy or intra-graft expression of pro-fibrotic mediators. Further, we examined expression of EDA cFN and total FN by whole splenocytes under conditions promoting various T-helper lineages. Conditions supporting regulatory T-cell (Treg) development were characterized by greatest production of total FN and EDA cFN, though EDA cFN to total FN ratios were highest in Th1 cultures. These findings indicate that recipient-derived EDA cFN is dispensable for acute allograft rejection responses but that it promotes the development of fibrosis associated with chronic rejection. Further, conditions favouring the development of regulatory T cells, widely considered graft-protective, may drive production of ECM molecules which

  3. The biology of acute transplant rejection.

    PubMed Central

    Tilney, N L; Kupiec-Weglinski, J W

    1991-01-01

    An intriguing and increasingly understood facet of immune responses is the ability of a recipient to destroy a foreign tissue or organ graft. The phenomenon of acute rejection of an allograft involves a series of complex and inter-related cellular and humoral events, culminating in graft death. Some of the current thinking surrounding this phenomenon is reviewed. PMID:1867525

  4. Reversal of Diabetes by Islet Transplantation: Vulnerability of the Established Allograft

    NASA Astrophysics Data System (ADS)

    Bowen, K. M.; Prowse, S. J.; Lafferty, K. J.

    1981-09-01

    Nonspecific stimulation of the immune system of CBA mice carrying a functional BALB/c islet allograft failed to trigger graft rejection. Only three of six animals rejected their graft when injected intravenously with 105, 106, and 107 peritoneal cells of BALB/c origin over a 3-month period commencing 100 days after transplantation.

  5. Normalizing Rejection.

    PubMed

    Conn, Vicki S; Zerwic, Julie; Jefferson, Urmeka; Anderson, Cindy M; Killion, Cheryl M; Smith, Carol E; Cohen, Marlene Z; Fahrenwald, Nancy L; Herrick, Linda; Topp, Robert; Benefield, Lazelle E; Loya, Julio

    2016-02-01

    Getting turned down for grant funding or having a manuscript rejected is an uncomfortable but not unusual occurrence during the course of a nurse researcher's professional life. Rejection can evoke an emotional response akin to the grieving process that can slow or even undermine productivity. Only by "normalizing" rejection, that is, by accepting it as an integral part of the scientific process, can researchers more quickly overcome negative emotions and instead use rejection to refine and advance their scientific programs. This article provides practical advice for coming to emotional terms with rejection and delineates methods for working constructively to address reviewer comments. PMID:26041785

  6. Recurrent Hepatitis C in Liver Allografts

    PubMed Central

    Demetris, A. J.; Eghtesad, B.; Marcos, A.; Ruppert, K.; Nalesnik, M. A.; Randhawa, P.; Wu, T.; Krasinskas, A.; Fontes, P.; Cacciarelli, T.; Shakil, A. O.; Murase, N.; Fung, J. J.; Starzl, T. E.

    2010-01-01

    Rationale and Design The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an “immunosuppression minimization protocol” between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection. Results Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7–329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22–315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV. Conclusions Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV

  7. High expression of CD38, CD69, CD95 and CD154 biomarkers in cultured peripheral T lymphocytes correlates with an increased risk of acute rejection in liver allograft recipients.

    PubMed

    Boix, Francisco; Millan, Olga; Segundo, David San; Mancebo, Esther; Rimola, Antoni; Fabrega, Emilio; Fortuna, Virginia; Mrowiec, Anna; Castro-Panete, Maria J; Peña, Jesus de la; Llorente, Santiago; Minguela, Alfredo; Bolarin, Jose M; Paz-Artal, Estela; Lopez-Hoyos, Marcos; Brunet, Mercé; Muro, Manuel

    2016-05-01

    The mayor goal still outstanding into the solid organ transplantation field involves the search of surrogate biomarkers able to predict several clinical events, such as acute rejection (AR) or opportunistic infection. In the present multicenter study, a series of interesting surface antigens with important activator or inhibitory immune functions on cultured peripheral T cells were monitored in liver transplant recipients drawn at baseline and up to one year after transplantation. Sixty-four patients were included in the multicenter study during 3 years. Pre- and post-transplantation surface antigens levels displayed significant differences between AR and non acute rejection (NAR) groups, and also this differential expression was used to construct a risk predictive model based on a composite panel of outcome biomarkers (CD38, CD69, CD95 and CD154). The model was able to stratify these patients at high risk of AR. These preliminary results could provide basic information to improve the immunosuppressive treatment and it might better help to predict AR episodes. PMID:26850323

  8. Concentration of In-111-oxine-labeled autologous leukocytes in noninfected and nonrejecting renal allografts: concise communication

    SciTech Connect

    Collier, B.D.; Isitman, A.T.; Kaufman, H.M.; Rao, S.A.; Knobel, J.; Hellman, R.S.; Zielonka, J.S.; Pelc, L.

    1984-02-01

    Autologous leukocytes labeled with In-111 oxine (ILL) concentrated in the renal allografts of eight patients for whom transplant rejection, infection, or acute tubular necrosis (ATN) could be excluded. All patients had good-to-adequate renal function at the time of ILL scintigraphy, and none developed rejection or renal transplant failure during a 1-mo follow-up period. It is concluded that normally functioning renal allografts without evidence of rejection, infection, or ATN often will concentrate ILL. When a baseline study is not available for comparison, this phenomenon limits the value of ILL scintigraphy as a diagnostic test for transplant rejection or infection.

  9. Haptoglobin Enhances Cardiac Transplant Rejection

    PubMed Central

    Shen, Hua; Heuzey, Elizabeth; Mori, Daniel; Wong, Christine; Colangelo, Christopher; Chung, Lisa M.; Bruce, Can; Slizovskiy, Ilya B.; Booth, Carmen J.; Kreisel, Daniel; Goldstein, Daniel R.

    2015-01-01

    Rationale Early graft inflammation enhances both acute and chronic rejection of heart transplants, but it is unclear how this inflammation is initiated. Objective To identify specific inflammatory modulators and determine their underlying molecular mechanisms after cardiac transplantation. Methods and Results We used a murine heterotopic cardiac transplant model to identify inflammatory modulators of early graft inflammation. Unbiased mass spectrometric analysis of cardiac tissue before and up to 72 hours after transplantation revealed that 22 proteins including haptoglobin, a known anti-oxidant, are significantly upregulated in our grafts. Through the use of haptoglobin deficient mice, we show that 80% of haptoglobin deficient recipients treated with peri-operative administration of the costimulatory blocking agent CTLA4 immunoglobulin exhibited > 100 days survival of full major histocompatibility complex mismatched allografts, whereas all similarly treated wild type recipients rejected their transplants by 21 days post transplantation. We found that haptoglobin modifies the intra-allograft inflammatory milieu by enhancing levels of the inflammatory cytokine IL-6 and the chemokine MIP-2 but impair levels of the immunosuppressive cytokine IL-10. Haptoglobin also enhances dendritic cell graft recruitment and augments anti-donor T cell responses. Moreover, we confirmed that the protein is present in human cardiac allograft specimens undergoing acute graft rejection. Conclusions Our findings provide new insights into the mechanisms of inflammation after cardiac transplantation and suggest that, in contrast to its prior reported anti-oxidant function in vascular inflammation, haptoglobin is an enhancer of inflammation after cardiac transplantation. Haptoglobin may also be a key component in other sterile inflammatory conditions. PMID:25801896

  10. Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.

    PubMed

    Suhre, Karsten; Schwartz, Joseph E; Sharma, Vijay K; Chen, Qiuying; Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana M; Ding, Ruchuang; Ikle, David N; Bridges, Nancy D; Williams, Nikki M; Kastenmüller, Gabi; Karoly, Edward D; Mohney, Robert P; Abecassis, Michael; Friedewald, John; Knechtle, Stuart J; Becker, Yolanda T; Samstein, Benjamin; Shaked, Abraham; Gross, Steven S; Suthanthiran, Manikkam

    2016-02-01

    Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to-xanthosine ratio in urine samples. A composite signature of ratios of 3-sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3ε mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy. PMID:26047788

  11. Renal medullary changes in renal allograft recipients with raised serum creatinine

    PubMed Central

    Sis, B; Sarioglu, S; Celik, A; Kasap, B; Yildiz, S; Kavukcu, S; Gulay, H; Camsari, T

    2006-01-01

    Objective To test the hypothesis that the renal medulla may reflect rejection related changes and thus have a predictive value in the assessment of acute renal allograft rejection or chronic graft damage. Methods 75 post‐transplant biopsies from 57 patients were scored according to the Banff 1997 scheme. The biopsies with adequate cortical and medullary tissue (n = 23) were selected and medullary tissues were reviewed for rejection related lesions except intimal arteritis. Chronic damage was determined by image analysis depending on periodic acid‐methenamine silver (PAMS)‐Masson trichrome (MT) staining. Medullary and cortical changes were compared. Results Interstitial inflammation and tubulitis were more frequent and severe in the cortex (p<0.001). Medullary tubulitis was associated with intimal arteritis (p = 0.003, r = 0.598). Medullary interstitial inflammation (n = 8) and tubulitis (n = 4) were associated with cortical borderline changes (n = 5) or allograft rejection (n = 3). The sensitivity, specificity, and positive and negative predictive values of medullary inflammatory changes in predicting cortical allograft rejection were 43%, 69%, 37%, and 73%, respectively. A significant association was observed between medullary MT‐SAP and cortical PAMS‐SAP values (p = 0.02, R2 = 0.23). Conclusions Acute rejection related lesions are more common and severe in the cortex, and the renal medulla does not sufficiently reflect cortical rejection. The positive and negative predictive values of medullary changes for allograft rejection are low, and medullary inflammation is not a reliable indicator of allograft rejection. Increased medullary fibrosis is correlated with chronic cortical damage. PMID:16461569

  12. An immunomodulatory role for follistatin-like 1 in heart allograft transplantation.

    PubMed

    Le Luduec, J B; Condamine, T; Louvet, C; Thebault, P; Heslan, J-M; Heslan, M; Chiffoleau, E; Cuturi, M-C

    2008-11-01

    Donor-specific tolerance to heart allografts in the rat can be achieved by donor-specific blood transfusions (DST) before transplantation. We have previously reported that this tolerance is associated with strong leukocyte infiltration, and that host CD8(+) T cells and TGFbeta are required. In order to identify new molecules involved in the induction phase of tolerance, we compared tolerated and rejected heart allografts (suppressive subtractive hybridization) 5 days after transplantation. We identified overexpression of Follistatin-like 1 (FSTL1) transcript in tolerated allografts compared to rejected allografts or syngeneic grafts. We show that FSTL1 is overexpressed during both the induction and maintenance phase of tolerance, and appears to be specific to the tolerance model induced by DST. Analysis of graft-infiltrating cells revealed predominant expression of FSTL1 in CD8(+) T cells from tolerated grafts, and depletion of these cells prior to transplantation abrogated FSTL1 expression and heart allograft survival. Moreover, overexpression of FSTL1 by adenovirus gene transfer in vivo significantly prolonged allograft survival in association with inhibition of the proinflammatory cytokines, IL6, IL17 A and IFNgamma. Taken together, these results suggest that FSTL1 could be an active component of the mechanisms mediating heart allograft tolerance. PMID:18925901

  13. Role of interleukin-17A in early graft rejection after orthotopic lung transplantation in mice

    PubMed Central

    Chen, Qi-Rui; Wang, Li-Feng; Xia, Si-Si; Zhang, Ya-Mei; Xu, Jiang-Nan

    2016-01-01

    Background The cellular and molecular mechanisms underlying lung allograft rejection remain poorly understood. We investigated the potential role of interleukin (IL)-17A in lung transplant rejection in a mouse model, because previous studies in clinical and rodent models have implicated IL-17A in both acute and chronic rejection. Methods To generate an orthotopic lung transplantation model, lungs from C57BL/6 or BALB/c mice were transplanted into C57BL/6 mice (isograft and allograft models, respectively). The effects of anti-IL-17A treatment in allograft recipients were investigated. The histological features and rejection status of isografts and allografts were assessed at 3, 7, and 28 days after transplantation, and differences in graft infiltrating cells and mRNA expression of relevant cytokines were quantified at 3 and 7 days after transplantation. Results As expected, isografts showed no obvious signs of rejection, whereas allografts exhibited minimal-to-mild rejection (grade A1–A2) by day 3 and moderate-to-severe rejection (grade A3–A4) by day 7, without evidence of obliterative bronchiolitis (OB). However, by 28 days, evidence of OB was observed in 67% (2/3) of allografts and severe rejection (grade A4) was observed in all. IL-17 mRNA expression in allografts was increased with rejection, and interferon (IFN)-γ and IL-6 mRNA expression levels followed a similar pattern. In contrast, IL-22 expression in allografts was only slightly increased. Antibody (Ab) neutralization of IL-17A diminished the signs of acute rejection at 7 days after transplantation in allografts, and this early protection was accompanied by a decrease in cellular stress according to histological evaluation, suggesting the involvement of IL-17A in the development of early post-transplantation lesions. Conclusions Our data indicate that IL-17A is important in the pathophysiology of allograft rejection, and neutralization of IL-17A is a potential therapeutic strategy to preventing lung

  14. Kidney allograft survival in dogs treated with total lymphoid irradiation

    SciTech Connect

    Howard, R.J.; Sutherland, D.E.R.; Lum, C.T.; Lewis, W.I.; Kim, T.H.; Slavin, S.; Najarian, J.S.

    1981-02-01

    Total lymphoid irradiation (TLI) is immunosuppressive and, in rodents, can induce a state where transplantation of allogenic bone marrow results in chimerism and permanent acceptance of organ allografts from the donor strain. Twelve splenectomized dogs were treated with TLI (150 rads per fraction, total dose 1950 to 3000 rads) before bilateral nephrectomy and renal allotransplantation. Eight dogs received bone marrow from the kidney donor. In 13 untreated control dogs renal allografts functioned for a mean +- (SE) of 4.7 +- 0.3 days. In the four TLI treated dogs who did not receive bone marrow the renal allografts functioned for 15 to 76 days (two dogs died with functioning grafts). In the eight TLI treated dogs who received donor bone marrow, two died immediately after transplantation, two rejected at 3 and 13 days, one died at 13 days with a functioning graft, and two have had the grafts function for longer than 500 days. Chimerism was not detected in the one dog tested. The response of peripheral blood lymphocytes to stimulation with phytohemaglutinin and in mixed lymphocyte culture was suppressed for at least one month after TLI. The results confirm the immunosuppressive effect of TLI. The absence of kidney rejection in two recipients of donor bone marrow show the potential of this approach to induce long-term immunologic unresponsiveness as to an organ allograft, but the outcome is unpredictable and further experiments are needed to define the optimal conditions for administration of TLI and bone marrow to the recipients.

  15. Role of TDTH and Tc populations in organ graft rejection. I. Functional analysis of graft-infiltrating T cells

    SciTech Connect

    Stepkowski, S.M.; Duncan, W.R.

    1986-10-01

    To analyze the role of T cell subpopulations in the rejection of organ allografts, we developed a new model for obtaining large numbers of graft infiltrating cells (GICs). We isolated W3/25+ Th/DTH and OX8+ Ts/c from vascularized, irradiated rat spleen allografts. W3/25+ GICs obtained from spleen allografts transplanted to normal recipients were highly effective in eliciting cardiac allograft rejection when transferred to sublethally irradiated recipients, however, the OX8+ subset was incapable of eliciting rejection. On the other hand, when OX8+ GICs were obtained from spleen allografts transplanted to previously immunized recipients, they were as efficient as the W3/25+ Th/DTH subset in eliciting cardiac allograft destruction. These results indicate that the W3/25+, OX8- T cell is required for the rejection of primary organ allografts, but that the rejection of a secondary allograft by an immune recipient may be mediated, independently, by both W3/25+ and OX8+ cells.

  16. Significant prolongation of segmental pancreatic allograft survival in two species

    SciTech Connect

    Du Toit, D.F.; Heydenrych, J.J.

    1988-06-01

    A study was conducted to assess the suppression of segmental pancreatic allograft rejection by cyclosporine (CSA) alone in baboons and dogs, and subtotal marrow irradiation (TL1) alone and TL 1 in combination with CSA in baboons. Total pancreatectomy in the dog and primate provided a reliable diabetic model, induced an absolute deficiency of insulin and was uniformly lethal if not treated. Continuous administration of CSA in baboons resulted in modest allograft survival. As in baboons, dogs receiving CSA 25 mg/kg/d rendered moderate graft prolongation but a dose of 40 mg/kg/d resulted in significant graft survival (greater than 100 days) in 5 of 8 allograft recipients. Irradiation alone resulted in minimal baboon pancreatic allograft survival of 20 baboons receiving TL1 1,000 rad and CSA, 3 had graft survival greater than of 100 days. Of 15 baboons receiving TL1 800 rad and CSA, 6 had graft survival of greater than 100 days. In conclusion, CSA administration in dogs and TL1 in combination with CSA in baboons resulted in highly significant segmental pancreatic allograft survival.

  17. Emerging role of B cells in chronic allograft dysfunction

    PubMed Central

    Colvin, Robert B.; Hirohashi, Tsutomu; Farris, Alton B.; Minnei, Francesca; Collins, A. Bernard; Smith, R. Neal

    2015-01-01

    B cells have many possible mechanisms by which they can affect allograft survival, including antigen presentation, cytokine production, immune regulation, and differentiation into alloantibody-producing plasma cells. This report reviews the last mechanism, which the authors regard as most critical for the long-term survival of allografts, namely, the promotion of chronic rejection by alloantibodies. Chronic humoral rejection characteristically arises late after transplantation and causes transplant glomerulopathy, multilamination of peritubular capillary basement membranes, and C4d deposition in PTCs and glomeruli. Circulating antidonor human leukocyte antigen class II antibodies are commonly detected and may precede the development of graft injury. Prognosis is poor, especially when recognized after graft dysfunction has developed. Improved detection and treatment are critically needed for this common cause of late graft loss. PMID:21116310

  18. Skin allograft and vascularized composite allograft: potential for long-term efficacy in the context of lymphatic modulation.

    PubMed

    Rinkinen, Jacob; Selley, Ryan; Agarwal, Shailesh; Loder, Shawn; Levi, Benjamin

    2014-01-01

    Tissue transplantation restores form and function in burn patients. The treatment of burn injuries is influenced by severity, location, and the percentage of total body surface area. There have been a number of different techniques developed to temporize and repair the destroyed tissue. However, in patients with large wound burden, sufficient donor site tissue may not be available for autograft harvesting. Such extensive burns necessitate other temporary and permanent options for wound coverage such as skin or vascularized composite allografts (VCA). Rejection of these tissues presents an ongoing problem which is currently managed using a host of systemic immunosuppressive medications. This article discusses the mechanism behind the innate and adaptive immune systems rejection of the allografts. By understanding these pathways, various techniques using immunomodulatory protocols have led to increased allograft survival. However, our primary interest lies in the initial recognition of the graft. We tailor this article to have a specific emphasis on lymphatic modulation as a potential adjunctive therapy. Reviews of the studies evaluating the effect of lymph node modulation on graft survival are described with future implications to allograft transplant research. PMID:25051523

  19. Allograft Pancreatectomy: Indications and Outcomes.

    PubMed

    Nagai, S; Powelson, J A; Taber, T E; Goble, M L; Mangus, R S; Fridell, J A

    2015-09-01

    This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro-femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances. PMID:25912792

  20. Extramedullary hematopoiesis in renal allograft

    PubMed Central

    Chen, Guilan; Ali, Reza; Shuldberg, Mark M.; Bastani, Bahar; Brink, David S.

    2013-01-01

    Extramedullary hematopoiesis (EMH), defined as the presence of hematopoietic elements outside of the medullary cavity of bone, has been reported in patients with various hematopoietic neoplasms including myelofibrosis. EMH commonly occurs in the liver and spleen (resulting in hepatosplenomegaly) and uncommonly involves the kidney. EMH involving the allograft kidney has not been reported in English literature. Herein, we report the first case of EMH in allograft kidney in a patient with myelofibrosis. The clinical and pathological findings are described. Through comparison of the medullary neoplastic infiltrate with the renal allograft infiltrate, we postulate the neoplastic nature of the infiltrate in the allograft kidney. PMID:26120442

  1. Acute renal transplant rejection in children: assessment by Duplex Doppler sonography.

    PubMed

    Vergesslich, K A; Khoss, A E; Balzar, E; Schwaighofer, B; Ponhold, W

    1988-01-01

    Over a two year period 74 consecutive Duplex Doppler scans were performed in 23 children with renal allografts and were compared to the Doppler sonographic findings in orthotopic kidneys of 25 age matched healthy controls. The Doppler waveforms of renal arterial flow were analyzed qualitatively assessing systolic and diastolic flow amplitudes, for quantitation the Pourcelot index (PI) was used. There was no variation between the Doppler waveforms in recipients with normal allograft function and healthy controls. In 12 patients with biopsy proven acute rejection a decrease or absence of the diastolic flow amplitude was noted, resulting in increased pulsatility of the Doppler waveform. The mean PI in acute rejection differed significantly from the mean PI in normal allograft function. Duplex Doppler sonography is a useful imaging modality in the differentiation between acute rejection and normal allograft function and should therefore be integrated in the screening of children after renal transplantation. PMID:3054768

  2. Minimizing the risk of chronic allograft nephropathy.

    PubMed

    Weir, Matthew R; Wali, Ravinder K

    2009-04-27

    Chronic allograft nephropathy, now defined as interstital fibrosis and tubular atrophy not otherwise specified, is a near universal finding in transplant kidney biopsies by the end of the first decade posttransplantation. After excluding death with functioning graft, caused by cardiovascular disease or malignancy, chronic allograft nephropathy is the leading cause of graft failure. Original assumptions were that this was not a modifiable process but inexorable, likely due to past kidney injuries. However, newer understandings suggest that acute or subacute processes are involved, and with proper diagnosis, appropriate interventions can be instituted. Our method involved a review of the primary and secondary prevention trials in calcineurin inhibitor withdrawal. Some of the more important causes of progressive graft deterioration include subclinical cellular or humoral rejection, and chronic calcineurin inhibitor toxicity. Early graft biopsy, assessment of histology, and changes in immunosuppression may be some of the most important measures available to protect graft function. The avoidance of clinical inertia in pursuing subtle changes in graft function is critical. Modification in maintenance immunosuppression may benefit many patients with early evidence of graft deterioration. PMID:19384181

  3. Expanding the antibody-mediated component of plasma cell-rich acute rejection: A case series

    PubMed Central

    Uppin, M. S.; Gudithi, S.; Taduri, G.; Prayaga, A. K.; Raju, S. B.

    2016-01-01

    Renal allograft rejection is mediated by T-cells (T-cell mediated rejection) or by donor-specific antibodies (DSAs) (antibody mediated rejection, ABMR). Plasma cell-rich acute rejection (PCAR) is a unique entity due to its peculiar morphology and poor prognostic behavior. All allograft biopsies done at our center from January 2013 to October 2014 were reviewed, and seven were identified with a diagnosis of PCAR with antibody mediated rejection (ABMR). The allograft biopsies were classified as per the Banff 2007 schema. Immunohistochemistry with C4d, SV 40, CD3, CD20, CD138, kappa and lambda light chain was performed. Total 210 allograft biopsies were performed in the study period of which seven biopsies (3.3%) were diagnosed as PCAR with ABMR. All these were late ABMRs (more than 6 months) with median posttransplant duration of 17 months. The allograft biopsy showed features of PCAR along with glomerulitis, peritubular capillaritis, and positive C4d. DSA was positive in six patients. All the patients were treated with standard therapeutic measures of acute cellular rejection (ACR) and ABMR including steroids, plasma exchange, rituximab and intravenous immunoglobulins. All the patients had persistent graft dysfunction or graft loss on follow-up. PMID:27194831

  4. TLR Signals Promote IL-6/IL-17-Dependent Transplant Rejection1

    PubMed Central

    Chen, Luqiu; Ahmed, Emily; Wang, Tongmin; Wang, Ying; Ochando, Jordi; Chong, Anita S.; Alegre, Maria-Luisa

    2010-01-01

    Acute allograft rejection has often been correlated with Th1 differentiation, whereas transplantation tolerance is frequently associated with induction of regulation. The discovery of the Th17 phenotype has prompted its scrutiny in transplant rejection. Although IL-17 has recently been observed in settings of acute allograft rejection and drives rejection in T-bet-deficient mice that have impaired type 1 T cell responses, there is little evidence of its requirement during acute rejection in wild-type animals. We and others have previously shown that TLR9 signaling by exogenous CpG at the time of transplantation is sufficient to abrogate anti-CD154-mediated acceptance of fully mismatched cardiac allografts. In this study, we investigated the mechanism by which acute rejection occurs in this inflammatory context. Our results indicate that CpG targets recipient hematopoietic cells and that its pro-rejection effects correlate both with prevention of anti-CD154-mediated conversion of conventional CD4+ T cells into induced regulatory T cells (iTregs) and with the expression of IFN-γ and IL-17 by intra-graft CD4+ T cells. Moreover, the combined elimination of IL-6 and IL-17 signaling abrogated the ability of CpG to promote acute cardiac allograft rejection. Thus, pro-inflammatory signals at the time of transplantation can change the quality of the effector immune response and reveal a pathogenic function for IL-6 and IL-17 in wild-type recipients. PMID:19414775

  5. Transcript Signatures of Lymphocytic Bronchitis in Lung Allograft Biopsy Specimens

    PubMed Central

    Xu, Xiang; Golden, Jeffrey A.; Dolganov, Gregory; Jones, Kirk D.; Donnelly, Samantha; Weaver, Timothy; Caughey, George H.

    2008-01-01

    Background Rejection and obliterative bronchiolitis are barriers to sustained graft function in recipients of transplanted lungs. Early detection is hindered by inadequate tests and an incomplete understanding of the molecular events preceding or accompanying graft deterioration. Methods Hypothesizing that genes involved in immune responses and tissue remodeling produce biomarkers of rejection, we measured the expression of 192 selected genes in 72 sets of biopsy specimens from human lung allografts. Gene transcripts were quantified using a 2-step, multiplex, real-time polymerase chain reaction approach in endobronchial and transbronchial biopsy specimens from transplant recipients without acute infections undergoing routine surveillance bronchoscopy. Results Comparisons of histopathology in parallel biopsy specimens identified 6 genes correlating with rejection as manifested by lymphocytic bronchitis, a suspected harbinger of obliterative bronchiolitis. For example, β2-defensin and collagenase transcripts in inflamed bronchi increased 37-fold and 163-fold, respectively. By contrast, these transcripts did not correlate with acute rejection in transbronchial specimens. Further, no correspondence was noted between histopathologic bronchitis and parenchymal rejection when endobronchial and transbronchial samples were obtained from the same patient. Conclusions Our highly sensitive method permits quantitation of many gene transcripts simultaneously in small, bronchoscopically acquired biopsy specimens of allografts. Transcript signatures obtained by this approach suggest that airway and alveolar responses to rejection differ and that endobronchial biopsy specimens assess lymphocytic bronchitis and chronic rejection but are not proxies for transbronchial biopsy specimens. Further, they reveal changes in airway expression of the specific genes involved in host defense and remodeling and suggest that the measurement of transcripts correlating with lymphocytic bronchitis

  6. International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010.

    PubMed

    Mehra, Mandeep R; Crespo-Leiro, Maria G; Dipchand, Anne; Ensminger, Stephan M; Hiemann, Nicola E; Kobashigawa, Jon A; Madsen, Joren; Parameshwar, Jayan; Starling, Randall C; Uber, Patricia A

    2010-07-01

    The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology. PMID:20620917

  7. Apoptosis and expression of cytotoxic T lymphocyte effector molecules in renal allografts.

    PubMed

    Olive, C; Cheung, C; Falk, M C

    1999-03-01

    Cytotoxic T lymphocyte (CTL) mediated apoptosis is thought to play a major role in the rejection of renal allografts following transplantation, however, the CTL effector mechanism that is primarily responsible for immunological rejection is unknown. The two major effector pathways of CTL killing which lead to apoptosis involve the Fas/Fas ligand (Fas L) lytic pathway, and the perforin/granzyme degranulation pathway. The expression of CTL effector molecules which influence these pathways include Fas, Fas L and TiA-1 (cytotoxic granule protein). This study has investigated apoptosis by in situ terminal deoxytransferase-catalysed DNA nick end labelling (TUNEL), and the expression of CTL effector molecules by immunohistochemistry, in renal allograft biopsies obtained from patients following kidney transplantation. Renal biopsies were classified into three histological groups; acute cellular rejection, chronic rejection, or no rejection. The extent of T-cell infiltration of renal tissues was assessed by immunohistochemical staining with an anti-CD3 monoclonal antibody. Numerous TUNEL positive cells were detected in all transplant biopsies examined; these consisted mainly of renal tubular cells and infiltrating cells, with some TUNEL positive cells also detected in the glomeruli. In the case of normal kidney tissue, renal cells also stained positive for TUNEL but there was no lymphocytic infiltration. There was significantly more T-cell infiltration observed in acute rejection biopsies compared to the no rejection biopsies. In the case of Fas L expression, there was little expression in all three biopsy groups, apart from one case of chronic rejection. Conversely, although there were no significant differences in TiA-1 expression between the three biopsy groups, TiA-1 expression was more prominent in acute rejection biopsies. Furthermore, Fas expression was significantly decreased in acute rejection biopsies when compared to those of chronic and no rejection in which Fas

  8. Functional Immune Anatomy of the Liver-As an Allograft.

    PubMed

    Demetris, A J; Bellamy, C O C; Gandhi, C R; Prost, S; Nakanuma, Y; Stolz, D B

    2016-06-01

    The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system. PMID:26848550

  9. PD-L1 Deficiency within Islets Reduces Allograft Survival in Mice

    PubMed Central

    Ma, Dongxia; Duan, Wu; Li, Yakun; Wang, Zhimin; Li, Shanglin; Gong, Nianqiao; Chen, Gang; Chen, Zhishui; Wan, Chidan; Yang, Jun

    2016-01-01

    Background Islet transplantation may potentially cure type 1 diabetes mellitus (T1DM). However, immune rejection, especially that induced by the alloreactive T-cell response, remains a restraining factor for the long-term survival of grafted islets. Programmed death ligand-1 (PD-L1) is a negative costimulatory molecule. PD-L1 deficiency within the donor heart accelerates allograft rejection. Here, we investigate whether PD-L1 deficiency in donor islets reduces allograft survival time. Methods Glucose Stimulation Assays were performed to evaluate whether PD-L1 deficiency has detrimental effects on islet function. Islets isolated from PDL1-deficient mice or wild- type (WT) mice (C57BL/6j) were implanted beneath the renal capsule of streptozotocin (STZ)-induced diabetic BALB/c mice. Blood glucose levels and graft survival time after transplantation were monitored. Moreover, we analyzed the residual islets, infiltrating immune cells and alloreactive cells from the recipients. Results PD-L1 deficiency within islets does not affect islet function. However, islet PD-L1 deficiency increased allograft rejection and was associated with enhanced inflammatory cell infiltration and recipient T-cell alloreactivity. Conclusions This is the first report to demonstrate that PD-L1 deficiency accelerated islet allograft rejection and regulated recipient alloimmune responses. PMID:26990974

  10. Monitoring of canine pancreas allograft function with measurements of urinary amylase.

    PubMed

    Ekberg, H; Deane, S A; Allen, R D; Hawthorne, W J; Williamson, P; Grierson, J M; Stewart, G J; Little, J M

    1988-07-01

    A canine model of whole pancreas transplantation with pancreaticocystostomy was studied for predictability of graft rejection using urinary amylase (UA) monitoring. Six pancreatectomized dogs were transplanted without immunosuppression and with acute rejection occurring at a median of 9.5 days (range 7-12 days). A differential loss of allograft exocrine and endocrine function was demonstrated, with a gradual decrease in UA after transplantation but maintenance of fasting blood glucose levels (FBGL) till the day before complete loss of graft structure. Another 13 dogs treated with cyclosporin (25 mg/kg per day) had prolonged graft survival (P less than 0.01) with an actuarial median survival of 91 days (range 8-159 days). Five allografts were lost because of rejection and eight dogs died with functioning grafts. Fasting spot levels of UA less than 5000 iu/l or less than 10,000 iu/l had a positive predictivity of graft failure of 71% or 31%, respectively. Falls of UA levels of greater than 75% in 24 h and 48 h were seen equally in both rejecting and functioning allografts. This study confirmed the role of UA as an earlier marker of rejection than FBGL. The clinical role of UA will be important, but its use as a predictor of pancreas rejection may be dependent on a fall to a predetermined level rather than the rate of fall. PMID:2473736

  11. Neopterin and interferon gamma serum levels in renal allograft recipients.

    PubMed

    Khoss, A E; Balzar, E; Steger, H; Howanietz, H; Wladika, W; Hamilton, G; Woloszczuk, W

    In the follow-up of children receiving renal allografts the early differential diagnosis of infections and rejection episodes is the main problem. Serum levels of neopterin (N), a pteridine released from stimulated macrophages, was determined by radioimmunoassay. Also interferon-gamma (IF) serum levels, a marker of T lymphocyte activity, were determined with an immunoradiometric assay in 19 kidney-transplanted children. Both, infections and rejection episodes, are accompanied by distinct increases in N. The IF are elevated 1-3 days earlier than N, the median values during infections being significantly (p less than or equal to 0.001) higher than those during rejection crises. The routine measurement of N and IF allow the simple, quick and reliable monitoring of the immune status, which seems to be of a high relevance for the daily monitoring of transplant recipients. PMID:3150820

  12. Proteomics for rejection diagnosis in renal transplant patients: Where are we now?

    PubMed Central

    Gwinner, Wilfried; Metzger, Jochen; Husi, Holger; Marx, David

    2016-01-01

    Rejection is one of the key factors that determine the long-term allograft function and survival in renal transplant patients. Reliable and timely diagnosis is important to treat rejection as early as possible. Allograft biopsies are not suitable for continuous monitoring of rejection. Thus, there is an unmet need for non-invasive methods to diagnose acute and chronic rejection. Proteomics in urine and blood samples has been explored for this purpose in 29 studies conducted since 2003. This review describes the different proteomic approaches and summarizes the results from the studies that examined proteomics for the rejection diagnoses. The potential limitations and open questions in establishing proteomic markers for rejection are discussed, including ongoing trials and future challenges to this topic. PMID:27011903

  13. Proteomics for rejection diagnosis in renal transplant patients: Where are we now?

    PubMed

    Gwinner, Wilfried; Metzger, Jochen; Husi, Holger; Marx, David

    2016-03-24

    Rejection is one of the key factors that determine the long-term allograft function and survival in renal transplant patients. Reliable and timely diagnosis is important to treat rejection as early as possible. Allograft biopsies are not suitable for continuous monitoring of rejection. Thus, there is an unmet need for non-invasive methods to diagnose acute and chronic rejection. Proteomics in urine and blood samples has been explored for this purpose in 29 studies conducted since 2003. This review describes the different proteomic approaches and summarizes the results from the studies that examined proteomics for the rejection diagnoses. The potential limitations and open questions in establishing proteomic markers for rejection are discussed, including ongoing trials and future challenges to this topic. PMID:27011903

  14. MicroRNA-155 may affect allograft survival by regulating the expression of suppressor of cytokine signaling 1.

    PubMed

    Zhang, Maomao; Zhang, Qi; Liu, Fang; Yin, Li; Yu, Bo; Wu, Jian

    2011-10-01

    Immune rejection of organ transplants has life-threatening implications. It is believed that allograft rejection is initiated by the activation of lymphocytes following recognition of donor antigens, leading to generation of effector T lymphocytes, alloantibody production, and graft infiltration by alloreactive cells. There is solid evidence that miRNAs are integral for maintaining immune homeostasis and self-tolerance. A deeper understanding of the regulation of the immune response by miRNAs could define new mechanisms for manipulating graft immunity and preventing rejection. The miRNA miR-155 is of particular interest due to its known roles in regulating the expression of genes relevant to allograft rejection and the induction of immune tolerance. Indeed, miR-155 has been shown to dramatically impact both innate and adaptive immune processes, including inflammation, antigen presentation, T-cell differentiation, cytokine production, and T regulatory cell (Treg) functions. The suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of immune cell function and an evolutionarily conserved target of miR-155 in breast cancer cells. We propose that suppression of miR-155 could enhance SOCS1 expression in immune cells and suppress allograft rejection. Further studies on the specific role of miR-155 in allograft rejection may lead to the identification of new targets for therapeutic intervention. PMID:21802214

  15. The impact of TH17 cells on transplant rejection and the induction of tolerance

    PubMed Central

    Heidt, Sebastiaan; Segundo, David San; Wood, Kathryn J.

    2011-01-01

    Purpose of review This review aims to provide an overview of the latest evidence for the involvement of Th17 cells in the rejection of solid organ allografts. It will also consider the implications of the relationship between the differentiation pathways of Th17 and regulatory T cells (Tregs), as well as their plasticity in the context of transplantation tolerance. Recent findings In the absence of the Th1 lineage in vivo, Th17 cells are capable of rejecting cardiac allografts, showing the capacity of Th17 cells to cause allograft rejection, at least in experimental models. Th17 cells are relatively unsusceptible to suppression by Tregs, although this may be context dependent. Furthermore, addition of inflammatory signals to a Treg inducing environment leads to Th17 development and established Tregs can be converted to Th17 cells under inflammatory conditions. Summary The capacity of Th17 cells to cause allograft rejection is becoming increasingly clear. However, the role and contribution of Th17 cells in allograft rejection in the presence of the full orchestra of T helper cells remains elusive. The apparent resistance of Th17 to be suppressed by Tregs may pose a hurdle for effective immunosuppression and tolerance inducing protocols. Furthermore, the close developmental pathways of Th17 and Tregs and the ability of Tregs to convert into Th17 cells in the presence of inflammatory signals may impede the establishment of specific unresponsiveness to donor alloantigens in vivo. PMID:20616728

  16. Graft rejection by cytolytic T cells. Specificity of the effector mechanism in the rejection of allogeneic marrow

    SciTech Connect

    Nakamura, H.; Gress, R.E. )

    1990-02-01

    Cellular effector mechanisms of allograft rejection remain incompletely described. Characterizing the rejection of foreign-marrow allografts rather than solid-organ grafts has the advantage that the cellular composition of the marrow graft, as a single cell suspension, can be altered to include cellular components with differing antigen expression. Rejection of marrow grafts is sensitive to lethal doses of radiation in the mouse but resistant to sublethal levels of radiation. In an effort to identify cells mediating host resistance, lymphocytes were isolated and cloned from spleens of mice 7 days after sublethal TBI (650 cGy) and inoculation with allogeneic marrow. All clones isolated were cytolytic with specificity for MHC encoded gene products of the allogeneic marrow donor. When cloned cells were transferred in vivo into lethally irradiated (1025 cGy) recipients unable to reject allogeneic marrow, results utilizing splenic 125IUdR uptake indicated that these MHC-specific cytotoxic clones could suppress marrow proliferation. In order to characterize the effector mechanism and the ability of the clones to affect final engraftment, double donor chimeras were constructed so that 2 target cell populations differing at the MHC from each other and from the host were present in the same marrow allograft. Results directly demonstrated an ability of CTL of host MHC type to mediate graft rejection and characterized the effector mechanism as one with specificity for MHC gene products.

  17. Inability of donor total body irradiation to prolong survival of vascularized bone allografts: Experimental study in the rat

    SciTech Connect

    Gonzalez del Pino, J.; Benito, M.; Randolph, M.A.; Weiland, A.J. )

    1990-07-01

    At the present time, the toxic side effects of recipient immunosuppression cannot be justified for human non-vital organ transplantation. Total body irradiation has proven effective in ablating various bone-marrow-derived and endothelial immunocompetent cellular populations, which are responsible for immune rejection against donor tissues. Irradiation at a dose of 10 Gy was given to donor rats six days prior to heterotopic transplantation of vascularized bone allografts to host animals. Another group of recipient rats also received a short-term (sixth to fourteenth day after grafting), low dose of cyclosporine. Total body irradiation was able merely to delay rejection of grafts across a strong histocompatibility barrier for one to two weeks, when compared to nonirradiated allografts. The combination of donor irradiation plus cyclosporine did not delay the immune response, and the rejection score was similar to that observed for control allografts. Consequently, allograft viability was quickly impaired, leading to irreversible bone damage. This study suggest that 10 Gy of donor total body irradiation delivered six days prior to grafting cannot circumvent the immune rejection in a vascularized allograft of bone across a strong histocompatibility barrier.

  18. In situ expression of cytokines in human heart allografts.

    PubMed Central

    Van Hoffen, E.; Van Wichen, D.; Stuij, I.; De Jonge, N.; Klöpping, C.; Lahpor, J.; Van Den Tweel, J.; Gmelig-Meyling, F.; De Weger, R.

    1996-01-01

    Although allograft rejection, the major complication of human organ transplantation, has been extensively studied, little is known about the exact cellular localization of the cytokine expression inside the graft during rejection. Therefore, we used in situ hybridization and immunohistochemistry to study local cytokine mRNA and protein expression in human heart allografts, in relation to the phenotypical characteristics of the cellular infiltrate. Clear expression of mRNA for interleukin (IL)-6, IL-8, IL-9, and IL-10 and weak expression for IL-2, IL-4, IL-5, and tumor necrosis factor (TNF)-alpha was detected in biopsies exhibiting high rejection grades (grade 3A/B). Also at lower grades of rejection, mRNA for IL-6 and IL-9 was present. Some mRNA for IL-1 beta, TNF-beta, and interferon (IFN)-gamma was detected in only a few biopsies. Using immunohistochemistry, IL-2, IL-3, and IL-10 protein was detected in biopsies with high rejection grades, whereas few cells expressed IL-6, IL-8, and IFN-gamma. In biopsies with lower grades of rejection, a weaker expression of these cytokines was observed. IL-4 was hardly detected in any of the biopsies. The level of IL-12 expression was equal in all biopsies. Although mRNA expression of several cytokines was expressed at a low level compared with the protein level of those cytokines, there was a good correlation between localization of cytokine mRNA and protein. Expression of IL-2, IL-4, IL-5, TNF-alpha, and IFN-gamma was mainly detected in lymphocytes. IL-3, IL-6, IL-10, and IL-12 were not detected or not only detected in lymphocytes but also in other stromal elements (eg, macrophages). Macrophage production of IL-3 and IL-12 was confirmed by immunofluorescent double labeling with CD68. We conclude that cardiac allograft rejection is not simply regulated by T helper cell cytokine production, but other intragraft elements contribute considerably to this process. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:8952534

  19. Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts.

    PubMed

    Raissadati, Alireza; Nykänen, Antti I; Tuuminen, Raimo; Syrjälä, Simo O; Krebs, Rainer; Arnaudova, Ralica; Rouvinen, Eeva; Wang, Xiaomin; Poller, Wolfgang; Lemström, Karl B

    2015-12-01

    Obliterative bronchiolitis (OB) involves airway epithelial detachment, fibroproliferation, and inflammation, resulting in chronic rejection and transplant failure. Cysteine-rich 61 (CCN1) is an integrin receptor antagonist with a context-dependent role in inflammatory and fibroproliferative processes. We used a mouse tracheal OB model to investigate the role of CCN1 in the development of lung allograft OB. C57Bl/6 mice received a systemic injection of CCN1-expressing adenoviral vectors 2 days prior to subcutaneous implantation of tracheal allografts from major MHC-mismatched BALB/c mice. We treated another group of tracheal allograft recipients with cyclic arginine-glycine-aspartic acid peptide to dissect the role of αvβ3-integrin signaling in mediating CCN1 effects in tracheal allografts. Allografts were removed 4 weeks after transplantation and analyzed for luminal occlusion, inflammation, and vasculogenesis. CCN1 overexpression induced luminal occlusion (P < 0.05), fibroproliferation, and smooth muscle cell proliferation (P < 0.05). Selective activation of αvβ3-integrin receptor failed to mimic the actions of CCN1, and blocking failed to inhibit the effects of CCN1 in tracheal allografts. In conclusion, CCN1 exacerbates tracheal OB by enhancing fibroproliferation via an αvβ3-integrin-independent pathway. Further experiments are required to uncover its potentially harmful role in the development of OB after lung transplantation. PMID:26174800

  20. Sphingosine-1-phosphate receptor 1 agonist SEW2871 prolongs heterotopic heart allograft survival in mice.

    PubMed

    Ni, Qian; Yuan, Baohong; Liu, Tao; Lan, Fang; Luo, Xiaochun; Lu, Xiaoyan; Huang, Ping; Dai, Liangcheng; Jin, Xiaobao; Yin, Hui

    2015-05-01

    Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune cell trafficking. Recent studies have revealed immunomodulatory functions of S1P and its receptors (S1PR1-S1PR5) in many inflammatory conditions, such as asthma and autoimmunity. Here, we explore the efficacy of SEW2871, a selective S1PR1 agonist, in the prevention of acute allograft rejection in a murine cardiac transplantation model. Treatment of recipient mice with SEW2871 significantly prolongs cardiac allograft survival as compared to those recipients treated with control vehicle. The enhanced graft survival is associated with reduced circulating lymphocytes and allograft inflammatory cell infiltration. The cytokine analysis showed decreased allograft expression of TNF-α, IFN-γ and IL-2 in the SEW2871-treated mice. Moreover, administration of SEW2871 increases the percentage of CD4(+) T regulatory cells and FoxP3 expression in spleen of allograft recipients. Therefore, SEW2871 plays a critical role in regulation of lymphocyte trafficking and development, which directly contributes to prolongation of the allograft survival. PMID:25776899

  1. Transduction of interleukin-10 through renal artery attenuates vascular neointimal proliferation and infiltration of immune cells in rat renal allograft.

    PubMed

    Xie, Jingxin; Li, Xueyi; Meng, Dan; Liang, Qiujuan; Wang, Xinhong; Wang, Li; Wang, Rui; Xiang, Meng; Chen, Sifeng

    2016-08-01

    Renal transplantation is the treatment of choice for end-stage renal failure. Although acute rejection is not a major issue anymore, chronic rejection, especially vascular rejection, is still a major factor that might lead to allograft dysfunction on the long term. The role of the local immune-regulating cytokine interleukin-10 (IL-10) in chronic renal allograft is unclear. Many clinical observations showed that local IL-10 level was negatively related to kidney allograft function. It is unknown this negative relationship was the result of immunostimulatory property or insufficient immunosuppression property of local IL-10. We performed ex vivo transduction before transplantation through artery of the renal allograft using adeno-associated viral vectors carrying IL-10 gene. Twelve weeks after transplantation, we found intrarenal IL-10 gene transduction significantly inhibited arterial neointimal proliferation, the number of occluded intrarenal artery, interstitial fibrosis, peritubular capillary congestion and glomerular inflammation in renal allografts compared to control allografts receiving PBS or vectors carrying YFP. IL-10 transduction increased serum IL-10 level at 4 weeks but not at 8 and 12 weeks. Renal IL-10 level increased while serum creatinine decreased significantly in IL-10 group at 12 weeks compared to PBS or YFP controls. Immunohistochemical staining showed unchanged total T cells (CD3) and B cells (CD45R/B220), decreased cytotoxic T cells (CD8), macrophages (CD68) and increased CD4+ and FoxP3+ cells in IL-10 group. In summary, intrarenal IL-10 inhibited the allograft rejection while modulated immune response. PMID:27317647

  2. Aortic valve allografts in sheep

    PubMed Central

    Borrie, John; Hill, G. L.

    1968-01-01

    Some of the mechnical and biological problems surrounding the use of fresh allograft inverted aortic valves as mitral valve substitutes are described. Certain aspects of the problem have been studied experimentally. In three sheep `fresh' aortic valve allografts were inserted, using cardiopulmonary bypass, into the main pulmonary artery, and were observed from 5 to 7 months after operation. The animals survived normally. Their normal pulmonary valves remained in situ. The technique is described. At subsequent necropsy, macroscopically the valves were found to be free from vegetation, and the cusps were pliable and apparently normal. Microscopically, the supporting allograft myocardium showed necrosis and early calcification. The valve cusp showed hyalinization of collagen, although beneath the endocardium this hyalinized collagen contained moderate numbers of fibroblasts with no evidence of proliferation. The endocardium and arterial intima of the allograft showed evidence of ingrowth from adjacent normal host endocardial tissues. The allograft itself was invested in a loose layer of fibro-fatty tissue, which, in view of the necrotic state of the graft myocardium, could well have been a reparative reaction rather than a homograft reaction. It is concluded that, although the cusps could function normally, the necrosis of the myocardium might in time lead to late failure of the graft. Further studies with the valve inserted at mitral level are indicated. Images PMID:5656757

  3. Osteochondral Allograft of the Talus

    PubMed Central

    Bisicchia, Salvatore; Rosso, Federica; Amendola, Annunziato

    2014-01-01

    Osteochondral lesions of the talus are being recognized as an increasingly common injury. They are most commonly located postero-medially or antero-laterally, while centrally located lesions are uncommon. Large osteochondral lesions have significant biomechanical consequences and often require resurfacing with osteochondral autograft transfer, mosaicplasty, autologous chondrocyte implantation (or similar methods) or osteochondral allograft transplantation. Allograft procedures have become popular due to inherent advantages over other resurfacing techniques. Cartilage viability is one of the most important factors for successful clinical outcomes after transplantation of osteochondral allografts and is related to storage length and intra-operative factors. While there is abundant literature about osteochondral allograft transplantation in the knee, there are few papers about this procedure in the talus. Failure of non-operative management, initial debridement, curettage or microfractures are an indication for resurfacing. Patients should have a functional ankle motion, closed growth plates, absence of cartilage lesions on the tibial side. This paper reviews the published literature about osteochondral allograft transplantation of the talus focusing on indications, pre-operative planning, surgical approaches, postoperative management, results and complications of this procedure. PMID:25328456

  4. Biomechanical properties of bone allografts

    SciTech Connect

    Pelker, R.R.; Friedlaender, G.E.; Markham, T.C.

    1983-04-01

    The biomechanical properties of allograft bone can be altered by the methods chosen for its preservation and storage. These effects are minimal with deep-freezing or low-level radiation. Freeze-drying, however, markedly diminishes the torsional and bending strength of bone allografts but does not deleteriously affect the compressive or tensile strength. Irradiation of bone with more than 3.0 megarad or irradiation combined with freeze-drying appears to cause a significant reduction in breaking strength. These factors should be considered when choosing freeze-dried or irradiated allogeneic bone that will be subjected to significant loads following implantation.

  5. The treatment of peripheral nerve injuries using irradiated allografts and temporary host immunosuppression (in a rat model)

    SciTech Connect

    Easterling, K.J.; Trumble, T.E. )

    1990-10-01

    Irradiation of allografts prior to transplantation and host immunosuppression with cyclosporin-A were studied separately and in combination as means of lessening the rejection of transplanted peripheral nerve tissue. Lewis and Brown Norway rats were used in the animal model, as they differ at both major and minor histocompatibility loci. Sciatic nerve grafts (2.5 cm) were used and the animals were followed for 16 weeks after nerve grafting. The outcome was studied by functional measurements (sensory testing, gait analysis, joint flexion contracture, and muscle weight), as well as by measurements of biochemical and histologic parameters (hydroxyproline concentration and axon counts, respectively). Sensory testing was not reliable because of crossover innervation by the saphenous nerve. Evaluation by standard gait-testing techniques was found to be unsatisfactory. However, the allografted animals receiving cyclosporin-A had significantly smaller flexion contractures, compared to the allografted animals without immunosuppression (17 degrees +/- 12 degrees vs. 44 degrees +/- 13 degrees and 51 degrees +/- 13 degrees, p less than 0.005). Allografted animals receiving short-term cyclosporin-A had contractures that were not significantly different from those seen in isografted control animals (17 degrees +/- 12 degrees vs. 22 degrees +/- 15 degrees, NS). Muscle hydroxyproline concentration analysis revealed a lower hydroxyproline concentration among the allografted groups that received irradiated allografts, compared to groups receiving nonirradiated allogeneic grafts. The studies of muscle hydroxyproline concentration and muscle weight both showed substantial reinnervation, even in allografted animals without pretreatment of the grafts or immunosuppression of the recipient animal.

  6. Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates.

    PubMed

    Freitas, A M; Samy, K P; Farris, A B; Leopardi, F V; Song, M; Stempora, L; Strobert, E A; Jenkins, J A; Kirk, A D; Cendales, L C

    2015-08-01

    Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the nonlifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a nonhuman-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2(hi) memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model. PMID:26139552

  7. Treatment Modality Affects Allograft-Derived Schwann Cell Phenotype and Myelinating Capacity

    PubMed Central

    Hayashi, Ayato; Moradzadeh, Arash; Tong, Alice; Wei, Cindy; Tuffaha, Sami H.; Hunter, Daniel A.; Tung, Thomas H.; Parsadanian, Alexander; Mackinnon, Susan E.; Myckatyn, Terence M.

    2009-01-01

    We used peripheral nerve allografts, already employed clinically to reconstruct devastating peripheral nerve injuries, to study Schwann cell (SC) plasticity in adult mice. By modulating the allograft treatment modality we were able to study migratory, denervated, rejecting, and reinnervated phenotypes in transgenic mice whose SCs expressed GFP under regulatory elements of either the S100β (S100-GFP) or nestin (Nestin-GFP) promoters. Well-differentiated SCs strongly expressed S100-GFP, while Nestin-GFP expression was stimulated by denervation, and in some cases, axons were constitutively labeled with CFP to enable in vivo imaging. Serial imaging of these mice demonstrated that untreated allografts were rejected within 20 days. Cold preserved (CP) allografts required an initial phase of SC migration that preceded axonal regeneration thus delaying myelination and maturation of the SC phenotype. Mice immunosuppressed with FK506 demonstrated mild subacute rejection, but the most robust regeneration of myelinated and unmyelinated axons and motor endplate reinnervation. While characterized by fewer regenerating axons, mice treated with the co-stimulatory blockade (CSB) agents anti-CD40L mAb and CTLAIg-4 demonstrated virtually no graft rejection during the 28 day experiment, and had significant increases in myelination, connexin-32 expression, and Akt phosphorylation compared with any other group. These results indicate that even with SC rejection, nerve regeneration can occur to some degree, particularly with FK506 treatment. However, we found that co-stimulatory blockade facilitate optimal myelin formation and maturation of SCs as indicated by protein expression of myelin basic protein (MBP), connexin-32 and phospho-Akt. PMID:18514192

  8. Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

    NASA Technical Reports Server (NTRS)

    Sun, E.; Gao, Y.; Chen, J.; Roberts, A. I.; Wang, X.; Chen, Z.; Shi, Y.

    2004-01-01

    Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance.

  9. Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient.

    PubMed

    Sun, E; Gao, Y; Chen, J; Roberts, A I; Wang, X; Chen, Z; Shi, Y

    2004-12-01

    Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance. PMID:15375386

  10. Allograft pancreas: pale acinar nodules.

    PubMed

    Troxell, Megan L; Drachenberg, Cinthia

    2016-08-01

    Microscopic pale-staining acinar nodules were characterized in native pancreas in the 1980s under a variety of names but have been infrequently reported since. We retrospectively studied the frequency and characteristics of pale acinar nodules in allograft pancreas biopsies, as compared to a sampling of native pancreas specimens at our center. Pale acinar nodules were present in 13% (9/69) of allograft biopsies from 22% (7/32) of transplant patients, and 23% (5/22) of native pancreas surgical specimens, although more nodules per pancreas area were present in allograft needle biopsies. Acinar nodules had size of 100 to 700 μm, were periodic acid-Schiff pale, were synaptophysin negative, stained more weakly with keratin CAM 5.2 compared to surrounding parenchyma, and had a low proliferative rate. Ultrastructural evaluation revealed paucity of zymogen granules with dilated cistern-like structures. In our experience, pale acinar nodules have similar features in allograft and native pancreas specimens, yet remain of uncertain etiology and significance. PMID:27063474

  11. Emphysema in the renal allograft

    SciTech Connect

    Potter, J.L.; Sullivan, B.M.; Fluornoy, J.G.; Gerza, C.

    1985-04-01

    Two diabetic patients in whom emphysematous pyelonephritis developed after renal transplantation are described. Clinical recognition of this unusual and serious infection is masked by the effects of immunosuppression. Abdominal radiographic, ultrasound, and computed tomography findings are discussed. The clinical presentation includes urinary tract infection, sepsis, and acute tubular malfunction of the allograft in insulin-dependent diabetics.

  12. De novo C3 glomerulonephritis in a renal allograft.

    PubMed

    Nahm, Ji Hae; Song, Seung Hwan; Kim, Yu Seun; Cheong, Hae-Il; Lim, Beom Jin; Kim, Beom Seok; Jeong, Hyeon Joo

    2016-01-01

    C3 glomerulonephritis (C3GN) is a recently described, rare glomerular disease characterized by predominant or sole glomerular C3 deposits. Morphologic features of C3GN are similar to those of dense deposit disease (DDD); however, ribbon-like intramembranous electron-dense deposits are absent in the former. We report a case of de novo C3GN in a renal allograft with morphologic transformation to DDD. A 6-year-old boy presented with congenital left renal agenesis and right ureteropelvic junction obstruction. The patient underwent pyeloplasty but experienced recurrent urinary tract infections. At the age of 22 years, he received a renal allograft from a living related donor. C3GN was diagnosed after 1 year of transplantation; initial histology showed minimal mesangiopathy and this progressed to mesangial proliferation and membranoproliferative features over the next 7 years. Serum creatinine levels were stabilized with anti-rejection treatments for combating repeated episodes of acute rejection; however, glomerular and tubular band-like electron-dense deposits became evident. PMID:26986539

  13. [Chronic rejection: Differences and similarities in various solid organ transplants].

    PubMed

    Suhling, H; Gottlieb, J; Bara, C; Taubert, R; Jäckel, E; Schiffer, M; Bräsen, J H

    2016-01-01

    In this paper, chronic rejections after transplantation of the lungs, heart, liver, and kidney are described. Chronic allograft dysfunction (CAD) plays an important role in all of these transplantations and has a significant influence on patient survival. The pathophysiological reasons for CAD varies greatly in the various organs.Chronic lung allograft dysfunction (CLAD) is the most important determinant of survival and quality of life after lung transplantation. Diagnosis is based on lung function, especially forced expiratory flow in 1 s (FEV1) decline. Prevention, early detection, and rapid treatment are extremely important. Azithromycin and extracorporeal photopheresis are commonly used for treatment because they usually positively influence the progression of lung remodeling.The expression for chronic rejection of the heart is cardiac allograft vasculopathy (CAV). Immunological and nonimmunological factors are important for its development. Due to limited therapeutic options, prevention is of utmost importance (administration of mTOR inhibitors and minimizing cardiovascular risk factors).The mid- and long-term survival rates after liver transplantation have hardly changed in recent decades, which is an indication of the difficulty in diagnosing chronic graft dysfunction. Chronic ductopenic rejection accounts for a small proportion of late graft dysfunction. Idiopathic posttransplant hepatitis and de novo autoimmune hepatitis are important in addition to recurrence of the underlying disease that led to transplantation.Chronic allograft nephropathy is the result of severe rejection which cumulates in increasing fibrosis with remodeling. The earliest possible diagnosis and therapy is currently the only option. Diagnosis is based on evidence of donor-specific antibodies and histological findings. PMID:26782281

  14. The essential role of annexin A1 mimetic peptide in the skin allograft survival.

    PubMed

    Teixeira, Rodrigo Antonio Parra; Mimura, Kallyne Kioko Oliveira; Araujo, Leandro Pires; Greco, Karin Vicente; Oliani, Sonia Maria

    2016-02-01

    Immunosuppressive drugs have a critical role in inhibiting tissue damage and allograft rejection. Studies have demonstrated the anti-inflammatory effects of the annexin A1 (AnxA1) in the regulation of transmigration and apoptosis of leucocytes. In the present study, an experimental skin allograft model was used to evaluate a potential protective effect of AnxA1 in transplantation survival. Mice were used for the skin allograft model and pharmacological treatments were carried out using either the AnxA1 mimetic peptide Ac2-26, with or without cyclosporine A (CsA), starting 3 days before surgery until rejection. Graft survival, skin histopathology, leucocyte transmigration and expression of AnxA1 and AnxA5 post-transplantation were analysed. Pharmacological treatment with Ac2-26 increased skin allograft survival related with inhibition of neutrophil transmigration and induction of apoptosis, thereby reducing the tissue damage compared with control animals. Moreover, AnxA1 and AnxA5 expression increased after Ac2-26 treatment in neutrophils. Interestingly, the combination of Ac2-26 and cyclosporine A showed similar survival of transplants when compared with the cyclosporine A group, which could be attributed to a synergistic effect of both drugs. Investigations in vitro revealed that cyclosporine A inhibited extracellular-signal-regulated kinase (ERK) phosphorylation induced by Ac2-26 in neutrophils. Overall, the results suggest that AnxA1 has an essential role in augmenting the survival of skin allograft, mainly owing to inhibition of neutrophil transmigration and enhancement of apoptosis. This effect may lead to the development of new therapeutic approaches relevant to transplant rejection. PMID:23897745

  15. Predicting the development of cardiac allograft vasculopathy.

    PubMed

    Seki, Atsuko; Fishbein, Michael C

    2014-01-01

    Cardiac transplantation is a lifesaving therapy for patients with end-stage cardiovascular disease. There has been remarkable progress in controlling acute rejection, and the early survival rate after the heart transplantation has significantly improved. Cardiac allograft vasculopathy (CAV) is one of the common causes of death and a major limiting factor for long-term graft survival years after heart transplantation. CAV is a progressive occlusion of arteries and veins of the transplanted heart. CAV is often clinically silent because of the denervation of the transplanted heart. CAV tends to be found at an advanced stage of disease, including myocardial infarction (MI), congestive heart failure, arrhythmia, and/or sudden cardiac death. Because of the serious sequelae of CAV, risk factors, prevention, and prediction of CAV have been investigated. Despite the effort by many researchers, the pathogenesis is not yet completely understood. There are a number of both immune and nonimmune factors in the donor and recipient that are related to the development of CAV. In addition, several biomarkers in blood and tissue are found to correlate with the presence of CAV, and that may be able to predict CAV. Here, we review the pathology, pathogenesis, risk factors, diagnosis, and the potential for prediction of CAV. PMID:24972526

  16. Skin allografts in lethally irradiated animals repopulated with syngeneic hemopoietic cells

    SciTech Connect

    Schwadron, R.B.

    1983-01-01

    Total body irradiation and repopulation with syngeneic hemopoietic cells can be used to induce tolerance to major histocompatibility complex (MHC) mismatched heart and kidney grafts in rats and mice. However, this protocol does not work for MHC mismatched skin grafts in rats or mice. Furthermore, LEW rats that accept WF cardiac allografts after irradiation and repopulation reject subsequent WF skin grafts. Treatment of skin allograft donors with methotrexate prior to grafting onto irradiated and reconstituted mice resulted in doubling of the mean survival time. Analysis of which antigens provoked skin graft rejection by irradiation and reconstituted animals revealed the importance of I region antigens. Cardiac allograft acceptance by irradiated and reconstituted animals is mediated by suppressor cells found in the spleen. Adoptively tolerant LEW rats accepted WF skin grafts in 50% of grafted animals. Analysis of this phenomenon revealed that the adoptive transfer procedure itself was important in achieving skin allograft acceptance by these animals. In general, it seems that the lack of ability of irradiated and reconstituted animals to accept fully MHC disparate skin grafts results from the inability of these animals to suppress lymph node effector cells against I region antigen seen on highly immunogenic allogeneic Langerhans cells in the skin.

  17. Functional capacity and rehabilitation of recipients with a functioning renal allograft for ten years or more.

    PubMed

    Flechner, S M; Novick, A C; Braun, W E; Popowniak, K L; Steinmuller, D

    1983-06-01

    Forty-nine renal transplant recipients who had a single functioning allograft for ten or more years are reviewed. There were 17 cadaver recipients and 32 living-related recipients. Most patients have enjoyed excellent long-term renal function with stable mean daily dosages of azathioprine and prednisone. Fifty-three percent of patients never experienced a rejection episode, and 24% of patients experienced only one rejection episode. Five recipients (10%) developed malignancy following transplantation. Based on the Karnofsky activity scale, 80% of patients enjoyed unrestricted activity at ten years posttransplant. The two major factors contributing to declining activity were progression of systemic diseases such as atherosclerosis or diabetes, and declining allograft function. Following transplantation, all patients developed renewed interest in sexual activity, all men were potent, and all women experienced regular menses. Nine men achieved fatherhood and five women underwent successful pregnancy. Currently, 46 recipients are alive with a functioning allograft. These data confirm the ability of recipients with a long-term functioning renal allograft to return to the work force, participate in preillness levels of activity, and enjoy sexual activity and parenthood. PMID:6408771

  18. Bioengineering Thymus Organoids to Restore Thymic Function and Induce Donor-Specific Immune Tolerance to Allografts

    PubMed Central

    Fan, Yong; Tajima, Asako; Goh, Saik Kia; Geng, Xuehui; Gualtierotti, Giulio; Grupillo, Maria; Coppola, Antonina; Bertera, Suzanne; Rudert, William A; Banerjee, Ipsita; Bottino, Rita; Trucco, Massimo

    2015-01-01

    One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering. Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses against ovalbumin on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells. Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine. PMID:25903472

  19. Infrequency of cytomegalovirus genome in coronary arteriopathy of human heart allografts.

    PubMed Central

    Gulizia, J. M.; Kandolf, R.; Kendall, T. J.; Thieszen, S. L.; Wilson, J. E.; Radio, S. J.; Costanzo, M. R.; Winters, G. L.; Miller, L. L.; McManus, B. M.

    1995-01-01

    In heart transplantation, long-term engraftment success is severely limited by the rapid development of obliterative disease of the coronary arteries. Data from various groups have been suggestive of a pathogenetic role of herpesviruses, particularly human cytomegalovirus, in accelerated allograft coronary artery disease; however, results are not yet conclusive. This study examines the hypothesis that human cytomegalovirus infection of allograft tissues is related pathogenetically and directly to accelerated coronary artery disease. Using in situ DNA hybridization and polymerase chain reaction, we examined particular coronary artery segments from 41 human heart allografts (ranging from 4 days to greater than 4 years after transplantation; mean, 457 days) and 22 donor age- and gender-comparable, coronary site-matched trauma victims for presence of human cytomegalovirus DNA. Human cytomegalovirus genome was detected in 8 of 41 (19.5%) allografts and in 1 of 22 (4.5%) control hearts. This difference in positivity was not statistically significant (P = 0.10). In the human cytomegalovirus-positive hearts, viral genome was localized to perivascular myocardium or coronary artery media or adventitia. Human cytomegalovirus genome was not detected in arterial intima of any allograft or control heart, although human cytomegalovirus genome was readily identified within intima of small pulmonary arteries from lung tissue with human cytomegalovirus pneumonitis. By statistical analyses, the presence of human cytomegalovirus genome was not associated with the nature or digitized extent of transplant arteriopathy, evidence of rejection, allograft recipient or donor serological data suggestive of human cytomegalovirus infection, duration of allograft implantation, or causes of death or retransplantation. Thus, our data indicate a low frequency of detectable human cytomegalovirus genome in accelerated coronary artery disease and do not support a direct role for human cytomegalovirus

  20. Successful treatment of renal allograft and bladder malakoplakia with minimization of immunosuppression and prolonged antibiotic therapy.

    PubMed

    Graves, Angela L; Texler, Michael; Manning, Laurens; Kulkarni, Hemant

    2014-04-01

    Malakoplakia is an unusual granulomatous inflammatory disorder associated with diminished bactericidal action of leucocytes that occurs in immunosuppressed hosts. Cases of renal allograft malakoplakia are generally associated with a poor graft and patient survival. We present the case of a 56-year-old female with allograft and bladder malakoplakia occurring two years after renal transplantation complicated by an early antibody mediated rejection. Following a number of symptomatic urinary tract infections caused by resistant Gram-negative bacilli, a diagnosis of malakoplakia was made by biopsy of a new mass lesion of the renal allograft. Cystoscopy also revealed malakoplakia of the bladder wall. Immunosuppressant regimen was modified. Mycophenolate mofetil was ceased, prednisolone reduced to 5 mg/day and tacrolimus concentrations were carefully monitored to maintain trough serum concentrations of 2-4 μg/L. Concurrently, she received a prolonged course of intravenous antibiotics followed by 13 months of dual oral antibiotic therapy with fosfomycin and faropenem. This joint approach resulted in almost complete resolution of allograft malakoplakia lesions and sustained regression of bladder lesions on cystoscopy with histological resolution in bladder lesions. Her renal function has remained stable throughout the illness. If treated with sustained antimicrobial therapy and reduction of immunosuppression, cases of allograft malakoplakia may not necessarily be associated with poor graft survival. PMID:24460630

  1. Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression

    PubMed Central

    Wang, Xiaojie; Hao, Jianqiang; Leung, Gigi; Breitkopf, Trisia; Wang, Eddy; Kwong, Nicole; Akhoundsadegh, Noushin; Warnock, Garth L.; Shapiro, Jerry; McElwee, Kevin J.

    2015-01-01

    Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1) or fibroblasts (FB, group 2) under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P < 0.001) without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation. PMID:26000314

  2. Successful therapy with rituximab of refractory acute humoral renal transplant rejection: a case report.

    PubMed

    Celik, A; Saglam, F; Cavdar, C; Sifil, A; Atila, K; Sarioglu, S; Bora, S; Gulay, H; Camsari, T

    2008-01-01

    Acute humoral rejection (AHR) is generally less responsive to conventional anti-rejection treatment with consequent allograft losses. Therapeutic options include antilymphocyte antibody (ATG), intravenous immunglobulin (IVIG), plasmapheresis, or immunoadsorption with protein A together with intensification of immunsuppression with a tacrolimus/mycophenolate mofetil combination. This report describes a transplant recipient who responded to rituximab therapy as treatment for steroid-, ATG-, IVIG-, and plasmapheresis-resistant AHR. PMID:18261611

  3. The correlation of intragraft cytokine expression with rejection in rat small intestine transplantation.

    PubMed

    McDiarmid, S V; Farmer, D G; Kuniyoshi, J S; Robert, M; Khadavi, A; Shaked, A; Busuttil, R W

    1994-09-27

    Rejection continues to be a major cause of graft loss in small intestine transplantation (SIT). We have studied, by semiquantitative reverse transcriptase PCR (rtPCR), the intragraft expression of cytokines relevant to rejection in a rat model. Heterotopic SIT grafts were performed from Lewis x Brown Norway F1 donors into Lewis recipients. The isograft control was Lewis into Lewis. Five animals in each isograft and allograft group were sacrificed on POD 3, 5, 7, 8, 9, 10, 12, and 14. mRNA was isolated from portions of the terminal ileum and rtPCR performed to amplify message for interleukin-2 (IL-2), IL-2 receptor (IL-2R), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). Semiquantitative analysis was performed using 32P radionuclide incorporation and scintillation counting. The results were expressed as percent activity compared with beta-actin. Histologic correlation with cytokine expression was made. On POD 3 after SIT there was no evidence of rejection by histology and all cytokines studied showed no difference between the isograft and the allograft. On POD 5 the first evidence of mild rejection was seen on histology and IL-6, IFN-gamma, TNF-alpha showed a significant up regulation in the allograft that persisted through POD 14. mRNA for IL-2 was not significantly upregulated until POD 7 and persisted until POD 14. IL-2R was constitutively expressed in both isograft and allograft and was not a reliable predictor of rejection. Histologic rejection was moderately severe by POD 7 and severe between POD 8 and 14 correlating with the increasing expression of IL-6, IFN-gamma, and TNF-alpha. In summary, we have shown that increasing expression of mRNA for IL-6, IFN-gamma, and TNF-alpha not only correlated with severity of rejection but that upregulation began early when histologic evidence of rejection first occurred. PMID:7940688

  4. Urinary cell mRNA profiles predictive of human kidney allograft status.

    PubMed

    Lee, John R; Muthukumar, Thangamani; Dadhania, Darshana; Ding, Ruchuang; Sharma, Vijay K; Schwartz, Joseph E; Suthanthiran, Manikkam

    2014-03-01

    Kidney allograft status is currently characterized using the invasive percutaneous needle core biopsy procedure. The procedure has become safer over the years, but challenges and complications still exist including sampling error, interobserver variability, bleeding, arteriovenous fistula, graft loss, and even death. Because the most common type of acute rejection is distinguished by inflammatory cells exiting the intravascular compartment and gaining access to the renal tubular space, we reasoned that a kidney allograft may function as an in vivo flow cytometer and sort cells involved in rejection into urine. To test this idea, we developed quantitative polymerase chain reaction (PCR) assays for absolute quantification of mRNA and pre-amplification protocols to overcome the low RNA yield from urine. Here, we review our single center urinary cell mRNA profiling studies that led to the multicenter Clinical Trials in Organ Transplantation (CTOT-04) study and the discovery and validation of a 3-gene signature of 18S rRNA-normalized measures of CD3ε mRNA and IP-10 mRNA and 18S rRNA that is diagnostic and predictive of acute cellular rejection in the kidney allograft. We also review our development of a 4-gene signature of mRNAs for vimentin, NKCC2, E-cadherin, and 18S rRNA diagnostic of interstitial fibrosis/tubular atrophy (IF/TA). PMID:24517436

  5. Frequency of HLA-G exon 8 polymorphisms and kidney allograft outcome in Iranian population.

    PubMed

    Aghdaie, Mahdokht H; Azarpira, Negar; Kazemi, Kurosh; Geramizadeh, Bita; Darai, Masumeh; Malekhoseini, Seid Ali

    2011-06-01

    The 14-bp polymorphism in exon 8 of the HLA-G gene is associated with HLA-G mRNA stability and the patterns of alternative isoform splicing and may influence the functionality of the HLA-G molecule. HLA-G expression was related to allograft acceptance and fewer episodes of acute rejection during heart, kidney and liver-kidney transplantation. In order to determine a possible correlation between the 14-bp insertion/deletion polymorphism and kidney allograft outcome in our population, genomic DNA was isolated from 144 patients who had received isolated kidney allografts. The recipients was divided into two groups, grafts presenting features of rejection group and a non-rejection group, and compared them with a control group of 100 healthy subjects. There was no significant difference in allelic frequencies of 14-bp insertion/deletion polymorphism between normal controls and kidney transplant patients. No significant difference was found between the RG and the NRG regarding the 14-bp genotypes and alleles. Therefore, additional studies with more sample size from other populations with analysis of other HLA-G polymorphisms are necessary to define this polymorphism as a valuable clinical marker. PMID:21107725

  6. Tubular and endothelial chimerism in renal allografts using fluorescence and chromogenic in situ hybridization (FISH, CISH) technology.

    PubMed

    Varga, Zsuzsanna; Gaspert, Ariana; Behnke, Silvia; von Teichman, Adriana; Fritzsche, Florian; Fehr, Thomas

    2012-04-01

    The role of endothelial and tubular chimerism in renal allograft adaptation and rejection varies in different studies. We addressed the correlation between different clinico-pathological settings and sex-chromosomal endothelial and/or tubular chimerism in renal allografts. We examined the presence or absence of the X and Y chromosomes by fluorescence and chromogenic in situ hybridization (FISH, CISH) methodology on paraffin embedded kidney biopsies in 16 gender mismatched renal transplants (1 to 12 years post-transplantation). Twelve patients were male, four female. Four groups were selected: (i) Vascular calcineurin inhibitor toxicity without rejection; (ii) T-cell mediated vascular rejection; (iii) antibody mediated rejection; and (iv) C4d-positivity in AB0-incompatible transplants with or without rejection. Twelve non-transplant kidney biopsies (8 female, 4 male) were used as controls. Tubular chimerism was detected more frequently (69%) than endothelial chimerism (12%) in renal transplants. One of 12 control patients had tubular and endothelial chimeric cells (8%). The Y chromosome occurred in 8/12 male recipients (67%) in tubular epithelial cells and in 5/12 male recipients (42%) in endothelial cells. Double X chromosomes were detected in 3/4 female recipients in tubular epithelium. Tubular chimerism occurred more often with endothelial chimerism and capillaritis without correlation with other parameters, such as rejection. Combined Y chromosomal tubular and lymphatic endothelial chimerism correlated with T-cell mediated vascular rejection in two out of three patients (66%). Combined Y chromosomal tubular and peritubular capillary chimerism correlated with antibody mediated C4d+ rejection in one out of two patients (50%). Tubular and/or endothelial chimerism occur frequently in gender mismatched renal allografts and, when combined, this is associated with T-cell mediated rejection. PMID:22449229

  7. Expression of Tumor Necrosis Factor in Human Acute Cardiac Rejection

    PubMed Central

    Arbustini, Eloisa; Grasso, Maurizia; Diegoli, Marta; Bramerio, Manuela; Foglieni, Andrea Scotti; Albertario, Marco; Martinelli, Luigi; Gavazzi, Antonello; Goggi, Claudio; Campana, Carlo; Vigano, Mario

    1991-01-01

    The authors performed an immunohistochemical study on expression of tumor necrosis factor alpha (TNFα) in endomyocardial biopsies from human cardiac allografts. TNFα immunoreactivity was found in 45% biopsies with mild acute rejection, in 83% biopsies with focal moderate rejection, in 80% biopsies with diffuse moderate rejection. Biopsies with absent rejection did not show immunoreactive cells. In mild rejection, positive cells were few and scanty monocytes and macrophages (MAC-387 and LN5 positive cells) and T lymphocytes (UCHL-1/CD45 RO positive cells) (up to 20% of all infiltrating cells). Expression of major histocompatibility complex (MHC) class II antigens on infiltrating and endothelial cells occurred earlier and independent of TNFα reactivity. Number of immunoreactive cells increased in moderate rejection (up to 50%). Immunoreactivity was also present in nonpigmented macrophages in part of the biopsies with resolving rejection (45%). The authors conclude that TNFα is expressed in acute cardiac rejection by immunologically activated inflammatory cells. Immunoreactive cells increase in number with increasing severity of the reaction. ImagesFigure 1Figure 2Figure 3Figure 4 PMID:1928295

  8. Leiomyoma in a Renal Allograft.

    PubMed

    Li, Yan Jun; Siriwardana, Amila Rohan; Symons, James Lawrence Penn; O'Neill, Gordon Francis; Qiu, Min Ru; Furlong, Timothy John

    2016-01-01

    Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year. PMID:27195169

  9. Leiomyoma in a Renal Allograft

    PubMed Central

    Li, Yan Jun; Siriwardana, Amila Rohan; Symons, James Lawrence Penn; O'Neill, Gordon Francis; Qiu, Min Ru; Furlong, Timothy John

    2016-01-01

    Leiomyomas are smooth muscle tumours that are rarely found in the kidney. There is one report of a leiomyoma in a kidney transplant in a paediatric recipient. Here, we report an adult renal transplant recipient who developed an Epstein-Barr virus-positive leiomyoma in his allograft 15 years after transplantation. The patient was converted to everolimus for posttransplant immunosuppression management and there was no sign of progression over a year. PMID:27195169

  10. Microvascular destruction identifies murine allografts that cannot be rescued from airway fibrosis

    PubMed Central

    Babu, Ashok N.; Murakawa, Tomohiro; Thurman, Joshua M.; Miller, Edmund J.; Henson, Peter M.; Zamora, Martin R.; Voelkel, Norbert F.; Nicolls, Mark R.

    2007-01-01

    Small airway fibrosis (bronchiolitis obliterans syndrome) is the primary obstacle to long-term survival following lung transplantation. Here, we show the importance of functional microvasculature in the prevention of epithelial loss and fibrosis due to rejection and for the first time, relate allograft microvascular injury and loss of tissue perfusion to immunotherapy-resistant rejection. To explore the role of alloimmune rejection and airway ischemia in the development of fibroproliferation, we used a murine orthotopic tracheal transplant model. We determined that transplants were reperfused by connection of recipient vessels to donor vessels at the surgical anastomosis site. Microcirculation through the newly formed vascular anastomoses appeared partially dependent on VEGFR2 and CXCR2 pathways. In the absence of immunosuppression, the microvasculature in rejecting allografts exhibited vascular complement deposition, diminished endothelial CD31 expression, and absent perfusion prior to the onset of fibroproliferation. Rejecting grafts with extensive endothelial cell injury were refractory to immunotherapy. After early microvascular loss, neovascularization was eventually observed in the membranous trachea, indicating a reestablishment of graft perfusion in established fibrosis. One implication of this study is that bronchial artery revascularization at the time of lung transplantation may decrease the risk of subsequent airway fibrosis. PMID:18060031

  11. Trichinella spiralis infection changes immune response in mice performed abdominal heterotopic cardiac transplantation and prolongs cardiac allograft survival time.

    PubMed

    Deng, Gengguo; Deng, Ronghai; Yao, Jianping; Liao, Bing; Chen, Yinghua; Wu, Zhongdao; Hu, Hongxing; Zhou, Xingwang; Ma, Yi

    2016-01-01

    Allograft rejection has been an obstacle for long-term survival of patients for many years. Current strategies for transplant rejection are not as optimal as we expected, especially for long-term treatments. Trichinella spiralis, a nematode parasitized in mammalian muscle and as an invader, maintains harmonious with host in the long term by evading host immune attack. To determine whether T. spiralis infection impacts on allograft rejection, we performed mice cardiac allograft transplantation model by using BALB/c (H-2(b)) mice as donors and C57BL/6 (H-2(b)) mice orally infected with 300 muscle larvae for 28 days as recipients. Graft survival was monitored by daily palpation of the abdomen; histologic change was observed by H&E stain; and CD4(+), CD8(+), CD4(+)IFN-γ(+), and CD4(+)IL-17(+) T cells and regulatory T cells were examined with the use of flow cytometry. Serum cytokine levels were measured by Luminex. Finally, we found that mean survival time of cardiac allografts in T. spiralis group was 23.40 ± 1.99 days, while the vehicle control group was 10.60 ± 0.75 days. Furthermore, we observed alleviated histological changes in the heart allograft, decreased corresponding CD8(+) T cells, suppressed Th1 and Th17 responses, and increased regulatory T cell frequency in a murine cardiac transplantation model at day 7 post-transplantation in experimental group. These data suggest that T. spiralis infection resulted in prolonged allograft survival following murine cardiac transplantation, with suppressed Th1/Th17 responses and augmented regulatory T cells. PMID:26481486

  12. Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion.

    PubMed

    Guo, Zhong; Wang, Jun; Dong, Ying; Adams, Andrew B; Shirasugi, Nozomu; Kim, Oliver; Hart, John; Newton-West, Marvin; Pearson, Thomas C; Larsen, Christian P; Newell, Kenneth A

    2003-09-01

    Tolerance-inducing strategies that infuse donor bone marrow cells in conjunction with costimulation blockade have not been applied to intestinal transplantation. Intestines from BALB/c mice were transplanted into C57BL/6 recipients treated with anti-CD40L mAb, CTLA4-Ig, donor bone marrow, and busulfan. The majority of mice transplanted after completion of this regimen developed hematopoietic macrochimerism, although the degree of chimerism varied widely between recipients, and experienced long-term allograft survival. T cells from these mice demonstrated donor-specific hyporesponsiveness in vitro. However, T cells from chimeric mice proliferated to donor alloantigen in vivo. Furthermore, chimeric mice bearing intestinal allografts were capable of rejecting subsequently placed donor-strain skin grafts. These data suggest that although long-term allograft survival occurs in the absence of acute or chronic rejection, recipient mice are not completely unresponsive to donor alloantigens. When intestinal transplantation was performed at the time of initial bone marrow infusion (initiation of the chimerism protocol), most recipients failed to develop chimerism and promptly rejected the intestinal allograft. Although this is the most effective protocol that we have tested using this stringent model of transplantation, our observations suggest that modifications will be necessary before it can be reliably applied to the transplantation of highly immunogeneic organs like the intestine. PMID:12919088

  13. CD8+IL-17+ T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

    PubMed Central

    Dodd-o, Jeffrey M.; Coon, Tiffany A.; Miller, Hannah L.; Ganguly, Sudipto; Popescu, Iulia; O'Donnell, Christopher P.; Cardenes, Nayra; Levine, Melanie; Rojas, Mauricio; Weathington, Nathaniel M.; Zhao, Jing; Zhao, Yutong; McDyer, John F.

    2015-01-01

    Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet−/− recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet−/− recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8+ T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ–dominant responses in WT mice. CD4+ T cells produced IL-17 but not IFN-γ responses in T-bet−/− recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-γ+ responses in both T-bet−/− and WT mice but had no attenuating effect on lung rejection pathology in T-bet−/− recipients or on the development of obliterative airway inflammation that occurred only in T-bet−/− recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade–resistant rejection pathology and airway inflammation in T-bet−/− recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet−/− allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet–deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade–resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8+IL-17+ T cells. Our data support T-bet–deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation

  14. Sex-specific effects of carotenoid intake on the immunological response to allografts in guppies (Poecilia reticulata).

    PubMed

    Grether, Gregory F; Kasahara, Shinji; Kolluru, Gita R; Cooper, Edwin L

    2004-01-01

    Rarely are the evolutionary origins of mate preferences known, but, recently, the preference of female guppies (Poecilia reticulata) for males with carotenoid-based sexual coloration has been linked to a sensory bias that may have originally evolved for detecting carotenoid-rich fruits. If carotenoids enhance the immune systems of these fishes, as has been suggested for other species, this could explain the origin of the attraction to orange fruits as well as the maintenance of the female preference for orange males. We used the classic immunological technique of tissue grafting to assay a component of the immune response of guppies raised on two different dietary levels of carotenoids. Individual scales were transplanted between pairs of unrelated fishes, creating reciprocal allografts. Transplanted scales were scored on a six-point rejection scale every day for 10 days. Five days later, the same pairs of fishes received a second set of allografts and were scored again. Compared with low-carotenoid-diet males, high-carotenoid-diet males mounted a significantly stronger rejection response to the second allograft but not to the first allograft. High-carotenoid-diet females, however, showed no improvement in graft rejection compared with low-carotenoid-diet females. To our knowledge, this is the first experimental evidence for sex-specific effects of carotenoid consumption on the immune system of a species with carotenoid-based sexual coloration. These results are consistent with the hypothesis that the mate preference for carotenoid coloration is maintained by the benefits to females of choosing healthy mates, but they cast doubt on the idea that the benefits of carotenoid consumption, per se, could account for the origin of the preference. The sex-specificity of carotenoid effects on allograft rejection in guppies provides indirect support for the general hypothesis that males pay an immunological cost for sexual ornamentation. PMID:15002770

  15. Allografts in Soft Tissue Reconstructive Procedures

    PubMed Central

    Giedraitis, Andrius; Arnoczky, Steven P.; Bedi, Asheesh

    2014-01-01

    Context Allografts offer several important advantages over autografts in musculoskeletal reconstructive procedures, such as anterior cruciate ligament reconstruction. Despite growing widespread use of allograft tissue, serious concerns regarding safety and functionality remain. We discuss the latest knowledge of the potential benefits and risks of allograft use and offer a critical review of allograft tissue regulation, management, and sterilization to enable the surgeon to better inform athletes considering reconstructive surgery options. Evidence Acquisition A review of sources published in the past 10 years is the primary basis of this research. Study Design: Observational analysis (cohort study). Level of Evidence: Level 3. Results Comparable outcome data for autografts and allografts do not support universal standards for anterior cruciate ligament reconstruction, and physician recommendation and bias appear to significantly influence patient preference and satisfaction. Sterilization by gamma and electron-beam irradiation diminishes the biomechanical integrity of allograft tissue, but radioprotective agents such as collagen cross-linking and free radical scavengers appear to have potential in mitigating the deleterious effects of irradiation and preserving tissue strength and stability. Conclusion Allografts offer greater graft availability and reduced morbidity in orthopaedic reconstructive procedures, but greater expansion of their use by surgeons is challenged by the need to maintain tissue sterility and biomechanical functionality. Advances in the radioprotection of irradiated tissue may lessen concerns regarding allograft safety and structural stability. PMID:24790696

  16. Allograft Replacement for Absent Native Tissue

    PubMed Central

    Chaudhury, Salma; Wanivenhaus, Florian; Fox, Alice J.; Warren, Russell F.; Doyle, Maureen; Rodeo, Scott A.

    2013-01-01

    Context: Structural instability due to poor soft tissue quality often requires augmentation. Allografts are important biological substitutes that are used for the symptomatic patient in the reconstruction of deficient ligaments, tendons, menisci, and osteochondral defects. Interest in the clinical application of allografts has arisen from the demand to obtain stable anatomy with restoration of function and protection against additional injury, particularly for high-demand patients who participate in sports. Traditionally, allografts were employed to reinforce weakened tissue. However, they can also be employed to substitute deficient or functionally absent tissue, particularly in the sports medicine setting. Objective: This article presents a series of 6 cases that utilized allografts to restore functionally deficient anatomic architecture, rather than just simply augmenting the degenerated or damaged native tissue. Detailed discussions are presented of the use of allografts as a successful treatment strategy to replace functionally weakened tissue, often after failed primary repairs. PMID:24427387

  17. Organ transplant tissue rejection: detection and staging by fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    MacAulay, Calum E.; Whitehead, Peter D.; McManus, Bruce; Zeng, Haishan; Wilson-McManus, Janet; MacKinnon, Nick; Morgan, David C.; Dong, Chunming; Gerla, Paul; Kenyon, Jennifer

    1998-07-01

    Patients receiving heart or other organ transplants usually require some level of anti-rejection drug therapy, most commonly cyclosporine. The rejection status of the organ must be monitored to determine the optimal anti-rejection drug therapy. The current method for monitoring post-transplant rejection status of heart transplant patients consists of taking biopsies from the right ventricle. In this work we have developed a system employing optical and signal-processing techniques that will allow a cardiologist to measure spectral changes associated with tissue rejection using an optical catheter probe. The system employs time gated illumination and detection systems to deal with the dynamic signal acquisition problems associated with in vivo measurements of a beating heart. Spectral data processing software evaluates and processes the data to produce a simple numerical score. Results of measurements made on 100 excised transplanted isograft and allograft rat hearts have demonstrated the ability of the system to detect the presence of rejection and to accurately correlate the spectroscopic results with the ISHLT (International Society for Heart and Lung Transplantation) stage of rejection determined by histopathology. In vivo measurements using a pig transplant model are now in process.

  18. Osteochondral Allografts in the Ankle Joint

    PubMed Central

    Vannini, Francesca; Buda, Roberto; Ruffilli, Alberto; Cavallo, Marco; Giannini, Sandro

    2013-01-01

    Purpose: The aim of this systematic review is to report about the clinical use of partial and total fresh osteochondral allograft in the ankle joint. The state of the art of allografts with regard to basic science, procurement and storage methods, immunogenicity, generally accepted indications and contraindications, and the rationale of the allografting procedure have been described. Methods: All studies published in PubMed from 2000 to January 2012 addressing fresh osteochondral allograft procedures in the ankle joint were identified, including those that fulfilled the following criteria: (a) level I-IV evidence addressing the areas of interest outlined above; (b) measures of functional, clinical, or imaging outcome; and (c) outcome related to ankle cartilage lesions or ankle arthritis treated by allografts. Results: The analysis showed a progressively increasing number of articles from 2000. The number of selected articles was 14; 9 of those focused on limited dimension allografts (plugs, partial) and 5 on bipolar fresh osteochondral allografts. The evaluation of evidence level showed 14 case series and no randomized studies. Conclusions: Fresh osteochondral allografts are now a versatile and suitable option for the treatment of different degrees of osteochondral disease in the ankle joint and may even be used as total joint replacement. Fresh osteochondral allografts used for total joint replacement are still experimental and might be considered as a salvage procedure in otherwise unsolvable situations. A proper selection of the patients is therefore a key point. Moreover, the patients should be adequately informed about the possible risks, benefits, and alternatives to the allograft procedure. PMID:26069666

  19. Immunosuppression in cardiac graft rejection: A human in vitro model to study the potential use of new immunomodulatory drugs

    SciTech Connect

    Crescioli, Clara Squecco, Roberta; Cosmi, Lorenzo; Sottili, Mariangela; Gelmini, Stefania; Borgogni, Elisa; Sarchielli, Erica; Scolletta, Sabino; Francini, Fabio; Annunziato, Francesco; Vannelli, Gabriella Barbara; Serio, Mario

    2008-04-01

    CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFN{gamma} and TNF{alpha}{alpha}; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNF{alpha}-induced up-regulation of IFN{gamma}R. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor {gamma} agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFN{gamma}-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.

  20. The cellular lesion of humoral rejection: predominant recruitment of monocytes to peritubular and glomerular capillaries.

    PubMed

    Fahim, T; Böhmig, G A; Exner, M; Huttary, N; Kerschner, H; Kandutsch, S; Kerjaschki, D; Bramböck, A; Nagy-Bojarszky, K; Regele, H

    2007-02-01

    Accumulation of inflammatory cells within capillaries is a common morphologic feature of humoral renal allograft rejection and is most easily appreciated if it occurs in glomeruli. The aim of our study was to determine the amount and composition of immune cells within glomeruli and peritubular capillaries (PTC) in cellular and humoral allograft rejection. Immunofluorescent double-labeling for CD31 and CD3 or CD68 was used for phenotyping and enumerating immune cells within glomeruli and PTC. The major findings are: (1) accumulation of immune cells in PTC is far more common than it would be anticipated based on the assessment by conventional histology; (2) it is not the absolute number of immune cells accumulating within capillaries, but rather the composition of the intracapillary cell population that distinguishes humoral rejection from cellular rejection and (3) in C4d positive biopsies a predominantly monocytic cell population accumulates not only within glomeruli but also within PTC. The median value of monocyte/T-cell ratio within PTC was 2.3 in C4d positive biopsies but only 1 (p = 0.0008) in C4d negative biopsies. Given their prominent presence within capillaries and their extensive biological versatility monocytes might contribute to the capillary damage observed in acute and chronic allograft rejection. PMID:17283488

  1. Rational clinical trial design for antibody mediated renal allograft injury

    PubMed Central

    Sandal, Shaifali; Zand, Martin S.

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  2. Rational clinical trial design for antibody mediated renal allograft injury.

    PubMed

    Sandal, Shaifali; Zand, Martin S

    2015-01-01

    Antibody mediated renal allograft rejection is a significant cause of acute and chronic graft loss. Recent work has revealed that AMR is a complex processes, involving B and plasma cells, donor-specific antibodies, complement, vascular endothelial cells, NK cells, Fc receptors, cytokines and chemokines. These insights have led to the development of numerous new therapies, and adaptation of others originally developed for treatment of hemetologic malignancies, autoimmune and complement mediated conditions. Here we review emerging insights into the pathophysiology of AMR as well as current and emerging therapies for both acute and chronic AMR. Finally, we discuss rational clinical trial design in light of antibody and B cell immunobiology, as well as appropriate efficacy metrics to identify robust protocols and therapeutic agents. PMID:25553476

  3. Induction of tolerance to cardiac allografts in lethally irradiated rats reconstituted with syngeneic bone marrow

    SciTech Connect

    Hartnett, L.C.

    1983-01-01

    Generally, organ grafts from one individual animal to another are rejected in one-two weeks. However, if the recipients are given Total Body Irradiation (TBI) just prior to grafting, followed by reconstitution of hemopoietic function with syngeneic (recipient-type) bone marrow cells, then vascularized organ grafts are permanently accepted. Initially after irradiation, it is possible to induce tolerance to many strain combinations in rats. This thesis examines the system of TBI as applied to the induction of tolerance in LEW recipients of WF cardiac allografts. These two rat strains are mismatched across the entire major histocompatibility complex. When the LEW recipient are given 860 rads, a WF cardiac allograft and LEW bone marrow on the same day, 60% of the grafts are accepted. Methods employed to improve the rate of graft acceptance include: treating either donor or recipient with small amounts of methotrexate, or waiting until two days after irradiation to repopulate with bone marrow. It seems from these investigations of some of the early events in the induction of tolerance to allografts following TBI and syngeneic marrow reconstitution that an immature cell population in the bone marrow interacts with a radioresistant cell population in the spleen to produce tolerance to completely MHC-mismatched allografts.

  4. Induced regulatory T cells in allograft tolerance via transient mixed chimerism

    PubMed Central

    Hotta, Kiyohiko; Aoyama, Akihiro; Oura, Tetsu; Yamada, Yohei; Tonsho, Makoto; Huh, Kyu Ha; Kawai, Kento; Schoenfeld, David; Allan, James S.; Madsen, Joren C.; Benichou, Gilles; Smith, Rex-Neal; Colvin, Robert B.; Sachs, David H.; Cosimi, A. Benedict; Kawai, Tatsuo

    2016-01-01

    Successful induction of allograft tolerance has been achieved in nonhuman primates (NHPs) and humans via induction of transient hematopoietic chimerism. Since allograft tolerance was achieved in these recipients without durable chimerism, peripheral mechanisms are postulated to play a major role. Here, we report our studies of T cell immunity in NHP recipients that achieved long-term tolerance versus those that rejected the allograft (AR). All kidney, heart, and lung transplant recipients underwent simultaneous or delayed donor bone marrow transplantation (DBMT) following conditioning with a nonmyeloablative regimen. After DBMT, mixed lymphocyte culture with CFSE consistently revealed donor-specific loss of CD8+ T cell responses in tolerant (TOL) recipients, while marked CD4+ T cell proliferation in response to donor antigens was found to persist. Interestingly, a significant proportion of the proliferated CD4+ cells were FOXP3+ in TOL recipients, but not in AR or naive NHPs. In TOL recipients, CD4+FOXP3+ cell proliferation against donor antigens was greater than that observed against third-party antigens. Finally, the expanded Tregs appeared to be induced Tregs (iTregs) that were converted from non-Tregs. These data provide support for the hypothesis that specific induction of iTregs by donor antigens is key to long-term allograft tolerance induced by transient mixed chimerism. PMID:27446989

  5. Micro and nanoparticle drug delivery systems for preventing allotransplant rejection.

    PubMed

    Fisher, James D; Acharya, Abhinav P; Little, Steven R

    2015-09-01

    Despite decades of advances in transplant immunology, tissue damage caused by acute allograft rejection remains the primary cause of morbidity and mortality in the transplant recipient. Moreover, the long-term sequelae of lifelong immunosuppression leaves patients at risk for developing a host of other deleterious conditions. Controlled drug delivery using micro- and nanoparticles (MNPs) is an effective way to deliver higher local doses of a given drug to specific tissues and cells while mitigating systemic effects. Herein, we review several descriptions of MNP immunotherapies aimed at prolonging allograft survival. We also discuss developments in the field of biomimetic drug delivery that use MNP constructs to induce and recruit our bodies' own suppressive immune cells. Finally, we comment on the regulatory pathway associated with these drug delivery systems. Collectively, it is our hope the studies described in this review will help to usher in a new era of immunotherapy in organ transplantation. PMID:25937032

  6. Radiation sterilization of skin allograft

    NASA Astrophysics Data System (ADS)

    Kairiyama, E.; Horak, C.; Spinosa, M.; Pachado, J.; Schwint, O.

    2009-07-01

    In the treatment of burns or accidental loss of skin, cadaveric skin allografts provide an alternative to temporarily cover a wounded area. The skin bank facility is indispensable for burn care. The first human skin bank was established in Argentina in 1989; later, 3 more banks were established. A careful donor selection is carried out according to the national regulation in order to prevent transmissible diseases. As cadaveric human skin is naturally highly contaminated, a final sterilization is necessary to reach a sterility assurance level (SAL) of 10 -6. The sterilization dose for 106 batches of processed human skin was determined on the basis of the Code of Practice for the Radiation Sterilization of Tissue Allografts: Requirements for Validation and Routine Control (2004) and ISO 11137-2 (2006). They ranged from 17.6 to 33.4 kGy for bioburdens of >10-162.700 CFU/100 cm 2. The presence of Gram negative bacteria was checked for each produced batch. From the analysis of the experimental results, it was observed that the bioburden range was very wide and consequently the estimated sterilization doses too. If this is the case, the determination of a tissue-specific dose per production batch is necessary to achieve a specified requirement of SAL. Otherwise if the dose of 25 kGy is preselected, a standardized method for substantiation of this dose should be done to confirm the radiation sterilization process.

  7. Meniscal allograft transplantation in rabbit.

    PubMed

    Vilela, Liana M; Del Carlo, Ricardo J; Melo Filho, Edson V; Favarato, Lukiya S C; Duarte, Tatiana S; Pontes, Kelly C S; Cunha, Daise N Q

    2015-01-01

    This study evaluated the technique for meniscal allograft transplantation using allografts preserved in glycerin 98% in rabbits. Euthanasia was performed at 70 days to compare the transplanted (TM1 to TM16) versus the contralateral meniscus (OM1 to OM16). Sixteen menisci, 8 transplanted and 8 contralateral, were submitted to gross examination, histomorphometric analysis for identification and quantification of cellular type, and for quantification and distribution of collagen fibers. A revascularization study was conducted in all of the other samples. Lengths of the OM varied from 0.9 to 1.0 cm and two TM were smaller. All TM were completely attached to the synovial membrane, except for one case that presented partial fixation. Both, TM and OM had similar amounts of chondrocytes, fibroblasts and fibrocytes, and at the horns, chondrocytes were predominant. The collagen fibers in TM were well organized throughout the body, and disorganized at the horns. These fibers in OM were organized. The amounts of collagen type I and III, and the vascularization of the perimeniscal tissue and of the edge were similar in OM and TM. These results demonstrated graft integration and thus this transplantation technique and preservation method may be recommended. PMID:26648544

  8. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes.

    PubMed

    Braza, Faouzi; Brouard, Sophie; Chadban, Steve; Goldstein, Daniel R

    2016-05-01

    Graft inflammation impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection. Elucidating the mechanisms by which inflammation is induced after organ transplantation could lead to novel therapeutics to improve transplant outcomes. In this Review we describe endogenous substances - damage-associated molecular patterns (DAMPs) - that are released after allograft reperfusion and induce inflammation. We also describe innate immune signalling pathways that are activated after solid organ transplantation, with a focus on Toll-like receptors (TLRs) and their signal adaptor, MYD88. Experimental and clinical studies have yielded a large body of evidence that TLRs and MYD88 are instrumental in initiating allograft inflammation and promoting the development of acute and chronic rejection. Ongoing clinical studies are testing TLR inhibition strategies in solid organ transplantation, although avoiding compromising host defence to pathogens is a key challenge. Further elucidation of the mechanisms by which sterile inflammation is induced, maintained and amplified within the allograft has the potential to lead to novel anti-inflammatory treatments that could improve outcomes for solid organ transplant recipients. PMID:27026348

  9. Lung transplantation in the rat. III. Functional studies in iso- and allografts

    SciTech Connect

    Marck, K.W.; Prop, J.; Wildevuur, C.R.

    1983-08-01

    Recently a microsurgical technique for orthotopic left lung transplantation in the rat was developed. The aim of this study was to investigate the influence of the operation itself and of an unmodified rejection reaction on the function of the transplanted rat lung. Orthotopic left lung transplantation was performed in 59 rats (34 isografts and 25 allografts). Isografts demonstrated a mean left lung perfusion of 23.1% in the first two postoperative weeks. Seven out of the 10 animals, subjected to a repeated scintigraphy 5-10 weeks later, had an increased graft perfusion, resulting in an almost normal mean left lung perfusion of 34.8%. At that time chest roentgenography revealed a good aeration of the grafts, that at autopsy had a normal aspect. Allografts showed an initial mean left lung perfusion (24.6%) similar to the isografts, which, however, declined sharply a few days later (4.3%). At that time chest roentgenography revealed totally opalescent grafts that at autopsy had the hepatized aspect characteristic of lung allograft rejection. These results of isogeneic and allogeneic lung transplantation in the rat were comparable with those of canine auto- and allotransplantation. For immunogenetic and economical reasons lung transplantation in the rat is a good alternative animal model in lung transplantation research.

  10. Future of allografts in sports medicine.

    PubMed

    Harner, Christopher D; Lo, Marvin Y

    2009-04-01

    Allografts play a prominent role in sports medicine, and their usage has increased dramatically over the past few decades, but the role of allograft in the future of sports medicine largely depends on several factors: (1) the ability of the tissue banking industry to convince both surgeons and the general population that tissue procurement is safe and nearly disease-free, (2) the ability to sterilize tissue with minimal compromise to tissue integrity, (3) successful clinical outcomes with allograft, and (4) the advent of artificial scaffolds and ligaments that function as well. PMID:19306738

  11. Immune response and histology of humoral rejection in kidney transplantation.

    PubMed

    González-Molina, Miguel; Ruiz-Esteban, Pedro; Caballero, Abelardo; Burgos, Dolores; Cabello, Mercedes; Leon, Miriam; Fuentes, Laura; Hernandez, Domingo

    2016-01-01

    The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ. PMID:27267916

  12. Radiation sterilization of tissue allografts: A review

    PubMed Central

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-01-01

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

  13. Radiation sterilization of tissue allografts: A review.

    PubMed

    Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

    2016-04-28

    Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

  14. Circulating NK-cell subsets in renal allograft recipients with anti-HLA donor-specific antibodies.

    PubMed

    Crespo, M; Yelamos, J; Redondo, D; Muntasell, A; Perez-Saéz, M J; López-Montañés, M; García, C; Torio, A; Mir, M; Hernández, J J; López-Botet, M; Pascual, J

    2015-03-01

    Detection of posttransplant donor-specific anti-HLA antibodies (DSA) constitutes a risk factor for kidney allograft loss. Together with complement activation, NK-cell antibody-dependent cell mediated cytotoxicity (ADCC) has been proposed to contribute to the microvascular damage associated to humoral rejection. In the present observational exploratory study, we have tried to find a relationship of circulating donor-specific and non donor-specific anti-HLA antibodies (DSA and HLA non-DSA) with peripheral blood NK-cell subsets and clinical features in 393 renal allograft recipients. Multivariate analysis indicated that retransplantation and pretransplant sensitization were associated with detection of posttransplant DSA. Recipient female gender, DR mismatch and acute rejection were significantly associated with posttransplant DSA compared to HLA non-DSA. In contrast with patients without detectable anti-HLA antibodies, DSA and HLA non-DSA patients displayed lower proportions of NK-cells, associated with increased CD56(bright) and NKG2A(+) subsets, the latter being more marked in DSA cases. These differences appeared unrelated to retransplantation, previous acute rejection or immunosuppressive therapy. Although preliminary and observational in nature, our results suggest that the assessment of the NK-cell immunophenotype may contribute to define signatures of alloreactive humoral responses in renal allograft recipients. PMID:25656947

  15. Long-term Survival of Allograft Murine Islets Coated via Covalently Stabilized Polymers

    PubMed Central

    Rengifo, Hernán R.; Giraldo, Jaime A.; Labrada, Irayme; Stabler, Cherie L.

    2014-01-01

    Clinical islet transplantation (CIT) has emerged as a promising treatment option for type 1 diabetes mellitus (T1DM); however, the anti-rejection drug regimen necessary to mitigate allograft islet rejection is undesirable. The use of polymeric coatings to immunocamouflage the transplant from host immune attack has great potential. We have recently developed alginate and poly(ethylene glycol) (PEG)-based polymers, functionalized with azide and phosphine, respectively, which form spontaneous and chemoselective crosslinks via the bioorthogonal Staudinger ligation scheme. Herein, we explored the utility of these polymers to form immunoprotective, ultrathin coatings on murine primary pancreatic islets. Resulting coatings were nontoxic, with unimpaired glucose stimulated insulin secretion. Transplantation of coated BALB/c (H-2d) islets into streptozotozin-induced diabetic C57BL/6 (H-2b) resulted in prompt achievement of normoglycemia, at a rate comparable to controls. A significant subset of animals receiving coated islets (57%) exhibited long-term (> 100 d) function, with robust islets observed upon explantation. Control islets rejected after 15 d (+/− 9 d). Results illustrate the capacity of chemoselectively functionalized polymers to form coatings on islets, imparting no detrimental effect to the underlying cells, with resulting coatings exhibiting significant protective effects in an allograft murine model. PMID:24497465

  16. Prolonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation.

    PubMed

    Solini, Samantha; Aiello, Sistiana; Cassis, Paola; Scudeletti, Pierangela; Azzollini, Nadia; Mister, Marilena; Rocchetta, Federica; Abbate, Mauro; Pereira, Rafael Luiz; Noris, Marina

    2012-03-01

    One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation. Prolonged CI was associated with anticipation of proteinuria onset and graft function deterioration (ischemia: 90d; no ischemia: 150d), more severe tubular atrophy, interstitial fibrosis, and glomerulosclerosis, and increased mortality rate (180d survival, ischemia: 0%; no ischemia: 67%). In ischemic allografts, T and B cells were detected very early and were organized in inflammatory clusters. Higher expression of BAFF-R and TACI within the ischemic allografts indicates that B cells are mature and activated. As a consequence of B cell activity, anti-donor antibodies, glomerular C4d and IgG deposition, important features of chronic humoral rejection, appeared earlier in ischemic than in non-ischemic allograft recipients. Thus, prolonged CI time plays a main role in CAI development by triggering acceleration of cellular and humoral reactions of chronic rejection. Limiting CI time should be considered as a main target in kidney transplantation. PMID:22239163

  17. Enhancement by dimethyl myleran of donor type chimerism in murine recipients of bone marrow allografts

    SciTech Connect

    Lapidot, T.; Terenzi, A.; Singer, T.S.; Salomon, O.; Reisner, Y. )

    1989-05-15

    A major problem in using murine models for studies of bone marrow allograft rejection in leukemia patients is the narrow margin in which graft rejection can be analyzed. In mice irradiated with greater than 9 Gy total body irradiation (TBI) rejection is minimal, whereas after administration of 8 Gy TBI, which spares a significant number of clonable T cells, a substantial frequency of host stem cells can also be detected. In current murine models, unlike in humans, bone marrow allograft rejection is generally associated with full autologous hematopoietic reconstitution. In the present study, we investigated the effect of the myeloablative drug dimethyl myleran (DMM) on chimerism status following transplantation of T cell-depleted allogenic bone marrow (using C57BL/6 donors and C3H/HeJ recipients, conditioned with 8 Gy TBI). Donor type chimerism 1 to 2 months post-transplant of 1 to 3 x 10(6) bone marrow cells was markedly enhanced by using DMM one day after TBI and prior to transplantation. Conditioning with cyclophosphamide instead of DMM, in combination with 8 Gy TBI, did not enhance engraftment of donor type cells. Artificial reconstitution of T cells, after conditioning with TBI plus DMM, by adding mature thymocytes, or presensitization with irradiated donor type spleen cells 1 week before TBI and DMM, led to strong graft rejection and consequently to severe anemia. The anti-donor responses in these models were proportional to the number of added T cells and to the number of cells used for presensitization, and they could be neutralized by increasing the bone marrow inoculum.

  18. Adipose-Derived Stromal Cells Promote Allograft Tolerance Induction

    PubMed Central

    Anam, Khairul; Lazdun, Yelena; Gimble, Jeffrey M.; Elster, Eric A.

    2014-01-01

    Amputations and unsalvageable injuries with devastating tissue loss are common in the combat wounded. Reconstructive transplantation in the civilian setting using vascular composite allotransplants (VCAs) with multiple tissues (skin, muscle, nerve, bone) combined with long-term multidrug immunosuppression has been encouraging. However, skin rejection remains a critical complication. Adipose-derived stromal/stem cells (ASCs) are easily obtained from normal individuals in high numbers, precluding ex vivo expansion. The reparative function and paracrine immunomodulatory capacity of ASCs has gained considerable attention. The present study investigated whether ASCs facilitate long-term skin allograft survival. ASCs were isolated from fresh human subcutaneous adipose lipoaspirate. Full-thickness skin grafts from BALB/c mice were transplanted onto the dorsal flanks of C57BL/6 mice treated with five doses of anti-CD4/CD8 monoclonal antibodies (10 mg/kg) on days 0, +2, +5, +7, and +14 relative to skin grafting. A single nonmyeloablative low dose of busulfan (5 mg/kg) was given on day +5. Seven days after skin transplantation, ASCs (3 × 106) were infused i.v. with or without donor bone marrow cells (BMCs; 5 × 105). ASC+BMC coinfusion with minimal conditioning led to stable lymphoid and myeloid macrochimerism, deletion of alloreactive T cells, expansion of regulatory T cells, and long-term allograft survival (>200 days). ASCs constitutively produced high levels of anti-inflammatory/immunoregulatory factors such as prostaglandin E2, indoleamine 2,3-dioxygenase, APO-1/Fas (CD95), and programmed cell death-1 ligand-2. These findings serve as a foundation for developing a translational advanced VCA protocol, embodying both ASCs and low-dose donor BMCs, in nonhuman primates, with the goal of enhancing functional outcomes and eliminating the complications associated with long-term immunosuppression. PMID:25411475

  19. Graft-Infiltrating Macrophages Adopt an M2 Phenotype and Are Inhibited by Purinergic Receptor P2X7 Antagonist in Chronic Rejection.

    PubMed

    Wu, C; Zhao, Y; Xiao, X; Fan, Y; Kloc, M; Liu, W; Ghobrial, R M; Lan, P; He, X; Li, X C

    2016-09-01

    Macrophages exhibit diverse phenotypes and functions; they are also a major cell type infiltrating chronically rejected allografts. The exact phenotypes and roles of macrophages in chronic graft loss remain poorly defined. In the present study, we used a mouse heart transplant model to examine macrophages in chronic allograft rejection. We found that treatment of C57BL/6 mice with CTLA4 immunoglobulin fusion protein (CTLA4-Ig) prevented acute rejection of a Balb/c heart allograft but allowed chronic rejection to develop over time, characterized by prominent neointima formation in the graft. There was extensive macrophage infiltration in the chronically rejected allografts, and the graft-infiltrating macrophages expressed markers associated with M2 cells but not M1 cells. In an in vitro system in which macrophages were polarized into either M1 or M2 cells, we screened phenotypic differences between M1 and M2 cells and identified purinergic receptor P2X7 (P2x7r), an adenosine triphosphate (ATP)-gated ion channel protein that was preferentially expressed by M2 cells. We further showed that blocking the P2x7r using oxidized ATP (oATP) inhibited M2 induction in a dose-dependent fashion in vitro. Moreover, treatment of C57BL/6 recipients with the P2x7r antagonist oATP, in addition to CTLA4-Ig treatment, inhibited graft-infiltrating M2 cells, prevented transplant vasculopathy, and induced long-term heart allografts survival. These findings highlight the importance of the P2x7r-M2 axis in chronic rejection and establish P2x7r as a potential therapeutic target in suppression of chronic rejection. PMID:27575724

  20. Countering Rejection Anxiety.

    ERIC Educational Resources Information Center

    Hanselman, Peggy Riley

    1989-01-01

    Outlines a step-by-step approach for guidance counselors in holding a preliminary college planning conference with high school juniors and their families in order to help students subsequently deal with possible rejection from a college. (TE)

  1. The beginning of clinical tolerance in solid organ allografts.

    PubMed

    Monaco, Anthony P

    2004-06-01

    carefully supervised weaning of immunosuppressive drugs in controlled tolerance trials is not unreasonable, especially when monitored by protocol allograft biopsies. Initial results suggest that aggressively treated low-grade steroid-responsive rejection reactions in the absence of immune-mediated tissue destruction does not necessarily require resumption of high-dose immunosuppression. Finally, the role of donor bone marrow infusions in facilitating tolerance/hyporesponsiveness induction needs to be studied and expanded. PMID:15859922

  2. Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes

    SciTech Connect

    Eisen, H.J.; Eisenberg, S.B.; Saffitz, J.E.; Bolman, R.M. 3d.; Sobel, B.E.; Bergmann, S.R.

    1987-04-01

    To determine whether cardiac transplant rejection can be detected noninvasively with indium-111 (/sup 111/In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 muCi of autologous /sup 111/In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 +/- 7.0 (SD) in transplanted hearts undergoing rejection and 0.4 +/- 1.1 in native hearts on the day before animals were killed. In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 +/- 0.4) and increased to 22.9 +/- 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE greater than 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures.

  3. Development and Effects of FTY720 Ophthalmic Solution on Corneal Allograft Survival

    PubMed Central

    Liu, Zhaochuan; Lin, Haotian; Huang, Chulong; Chen, Wan; Xiang, Wu; Geng, Yu; Chen, Weirong

    2015-01-01

    Fingolimod (FTY720), a novel class of sphingosine 1-phosphate receptor modulators, has received special interest among ophthalmologists, particularly given that oral administration of FTY720 has proven to effectively treat corneal graft rejection in animal models. However, no studies have examined the performance of FTY720 as an ophthalmic solution in reducing corneal rejection in high-risk corneal rejection models, and the stability and ocular irritation profile of FTY720 ophthalmic solution are also unknown. Thus, we developed 0.1%, 0.2% and 0.5% FTY720 ophthalmic solutions and evaluated their chemical stabilities under various storage conditions with high- performance liquid chromatography. To investigate the ocular irritancy of the FTY720 ophthalmic solution, New Zealand albino rabbits were subjected to the Draize test. Furthermore, classic, well-established rat allogenic penetrating keratoplasty models were used to investigate the anti-rejection efficacy of the tested FTY720 ophthalmic solutions. We found that the non-irritating 0.5% FTY720 ophthalmic solution could prolong corneal allograft survival in rats with significant efficacy for about one month. Furthermore, no significant concentration changes occurred in any of the types of FTY720 ophthalmic solutions within three months. These results revealed crucial profiles of FTY720 ophthalmic solutions and warrant further investigation and optimization of FTY720 in the anti-rejection therapy after keratoplasty. PMID:26558849

  4. Recent advances in renal transplantation: antibody-mediated rejection takes center stage

    PubMed Central

    Chen, Chien Chia; Sicard, Antoine; Rabeyrin, Maud; Morelon, Emmanuel; Dubois, Valérie

    2015-01-01

    Overlooked for decades, antibodies have taken center stage in renal transplantation and are now widely recognized as the first cause of allograft failure. Diagnosis of antibody-mediated rejection has considerably improved with identification of antibody-mediated lesions in graft biopsies and advances made in the detection of circulating donor-specific antibodies. Unfortunately, this progress has not yet translated into better outcomes for patients. Indeed, in the absence of a drug able to suppress antibody generation by plasma cells, available therapies can only slow down graft destruction. This review provides an overview of the current knowledge of antibody-mediated rejection and discusses future interesting research directions. PMID:26097724

  5. Autograft Substitutes: Conduits and Processed Nerve Allografts.

    PubMed

    Safa, Bauback; Buncke, Gregory

    2016-05-01

    Manufactured conduits and allografts are viable alternatives to direct suture repair and nerve autograft. Manufactured tubes should have gaps less than 10 mm, and ideally should be considered as an aid to the coaptation. Processed nerve allograft has utility as a substitute for either conduit or autograft in sensory nerve repairs. There is also a growing body of evidence supporting their utility in major peripheral nerve repairs, gap repairs up to 70 mm in length, as an alternative source of tissue to bolster the diameter of a cable graft, and for the management of neuromas in non-reconstructable injuries. PMID:27094886

  6. Meniscal allograft transplantation: rationale for treatment.

    PubMed

    Smith, N A; Costa, M L; Spalding, T

    2015-05-01

    The anatomy and microstructure of the menisci allow the effective distribution of load across the knee. Meniscectomy alters the biomechanical environment and is a potent risk factor for osteoarthritis. Despite a trend towards meniscus-preserving surgery, many tears are irreparable, and many repairs fail. Meniscal allograft transplantation has principally been carried out for pain in patients who have had a meniscectomy. Numerous case series have reported a significant improvement in patient-reported outcomes after surgery, but randomised controlled trials have not been undertaken. It is scientifically plausible that meniscal allograft transplantation is protective of cartilage, but this has not been established clinically to date. PMID:25922450

  7. Effect of cyclosporine, total lymphoid irradiation, and cobra venom factor on hyperacute rejection

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Murphy, C.E.; Saad, T.; Abernethy, K.; Miller, D.; Bollinger, R.R.

    1985-09-01

    Transplantation into sensitized recipients is contraindicated due to the potential for hyperacute rejection. In order to study the mechanism of hyperacute rejection and the role of immunosuppression in the face of presensitization, we evaluated the effect of total lymphoid irradiation, cyclosporine, and cobra venom factor, alone and in combination, on hyperacute rejection of heterotopic rat heart allografts. Lewis rats were sensitized to strongly RT-1-incompatible ACI rats by three successive skin grafts. Heart allografts were then performed, and survived for a mean period of 15.7 +/- 7.4 hours. Neither preoperative treatment of hypersensitized rats with total lymphoid irradiation alone nor with cyclosporine (5 mg/kg/day) resulted in a prolongation of survival (20.4 +/- 16.6 hours and 35.6 +/- 6.2 hours, respectively). However, complement depletion using cobra venom factor significantly prolonged mean graft survival time to 114.4 +/- 31.0 hours (p less than 0.05). Cyclosporine (10 mg/kg/day) also significantly prolonged survival to 149 +/- 29 hours (p less than 0.01), but did not lower the antibody or complement levels. The addition of total lymphoid irradiation or cyclosporine to treatment with cobra venom factor did not result in longer survival than cobra venom factor alone. In conclusion, cobra venom factor and cyclosporine delay but do not prevent hyperacute rejection, while total lymphoid irradiation has no observable effect on hyperacute rejection.

  8. Noninvasive detection of graft rejection by in vivo (19) F MRI in the early stage.

    PubMed

    Flögel, U; Su, S; Kreideweiss, I; Ding, Z; Galbarz, L; Fu, J; Jacoby, C; Witzke, O; Schrader, J

    2011-02-01

    Diagnosis of transplant rejection requires tissue biopsy and entails risks. Here, we describe a new (19) F MRI approach for noninvasive visualization of organ rejection via the macrophage host response. For this, we employed biochemically inert emulsified perfluorocarbons (PFCs), known to be preferentially phagocytized by monocytes and macrophages. Isografts from C57BL/6 or allografts from C57B10.A mice were heterotopically transplanted into C57BL/6 recipients. PFCs were applied intravenously followed by (1) H/(19) F MRI at 9.4 T 24 h after injection. (1) H images showed a similar position and anatomy of the graft in the abdomen for both cases. However, corresponding (19) F signals were only observed in allogenic tissue. (1) H/(19) F MRI enabled us to detect the initial immune response not later than 3 days after surgery, when conventional parameters did not reveal any signs of rejection. In allografts, the observed (19) F signal strongly increased with time and correlated with the extent of rejection. In separate experiments, rapamycin was used to demonstrate the ability of (19) F MRI to monitor immunosuppressive therapy. Thus, PFCs can serve as positive contrast agent for the early detection of transplant rejection by (19) F MRI with high spatial resolution and an excellent degree of specificity due to lack of any (19) F background. PMID:21214858

  9. Chronic Renal Transplant Rejection and Possible Anti-Proliferative Drug Targets.

    PubMed

    Bhatti, Adnan Bashir; Usman, Muhammad

    2015-01-01

    The global prevalence of renal transplants is increasing with time, and renal transplantation is the only definite treatment for end-stage renal disease. We have limited the acute and late acute rejection of kidney allografts, but the long-term survival of renal tissues still remains a difficult and unanswered question as most of the renal transplants undergo failure within a decade of their transplantation. Among various histopathological changes that signify chronic allograft nephropathy (CAN), tubular atrophy, fibrous thickening of the arteries, fibrosis of the kidney interstitium, and glomerulosclerosis are the most important. Moreover, these structural changes are followed by a decline in the kidney function as well. The underlying mechanism that triggers the long-term rejection of renal transplants involves both humoral and cell-mediated immunity. T cells, with their related cytokines, cause tissue damage. In addition, CD 20+ B cells and their antibodies play an important role in the long-term graft rejection. Other risk factors that predispose a recipient to long-term graft rejection include HLA-mismatching, acute episodes of graft rejection, mismatch in donor-recipient age, and smoking. The purpose of this review article is the analyze current literature and find different anti-proliferative agents that can suppress the immune system and can thus contribute to the long-term survival of renal transplants. The findings of this review paper can be helpful in understanding the long-term survival of renal transplants and various ways to improve it. PMID:26677426

  10. Chronic Renal Transplant Rejection and Possible Anti-Proliferative Drug Targets

    PubMed Central

    Usman, Muhammad

    2015-01-01

    The global prevalence of renal transplants is increasing with time, and renal transplantation is the only definite treatment for end-stage renal disease. We have limited the acute and late acute rejection of kidney allografts, but the long-term survival of renal tissues still remains a difficult and unanswered question as most of the renal transplants undergo failure within a decade of their transplantation. Among various histopathological changes that signify chronic allograft nephropathy (CAN), tubular atrophy, fibrous thickening of the arteries, fibrosis of the kidney interstitium, and glomerulosclerosis are the most important. Moreover, these structural changes are followed by a decline in the kidney function as well. The underlying mechanism that triggers the long-term rejection of renal transplants involves both humoral and cell-mediated immunity. T cells, with their related cytokines, cause tissue damage. In addition, CD 20+ B cells and their antibodies play an important role in the long-term graft rejection. Other risk factors that predispose a recipient to long-term graft rejection include HLA-mismatching, acute episodes of graft rejection, mismatch in donor-recipient age, and smoking. The purpose of this review article is the analyze current literature and find different anti-proliferative agents that can suppress the immune system and can thus contribute to the long-term survival of renal transplants. The findings of this review paper can be helpful in understanding the long-term survival of renal transplants and various ways to improve it. PMID:26677426