Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the ␣1 domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time ؍ 5.5 ؉͞؊1.7 vs. 54.7 ؉͞؊3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.
SummaryBackground and objectives ABO-incompatible kidney transplant recipients may have a higher incidence of BK virus allograft nephropathy (BKVAN) compared with ABO-compatible recipients. It is unclear whether HLAincompatible recipients share this risk or whether this phenomenon is unique to ABO-incompatible recipients.Design, setting, participation, & measurements This study analyzed adult incompatible kidney transplant recipients from 1998 to 2010 (62 ABO-incompatible and 221 HLA-incompatible) and identified patients in whom BKVAN was diagnosed by biopsy (per protocol or for cause). This was a retrospective analysis of a prospectively maintained database that compared BKVAN incidence and outcomes between ABO-and HLA-incompatible recipients, respectively. BKVAN link to rejection and graft accommodation phenotype were also explored. The Johns Hopkins Institutional Review Board approved this study.Results Risk for BKVAN was greater among ABO-incompatible than HLA-incompatible patients (17.7% versus 5.9%; P=0.008). Of BKVAN cases, 42% were subclinical, diagnosed by protocol biopsy. ABO-incompatibility and age were independent predictors for BKVAN on logistic regression. C4d deposition without histologic features of glomerulitis and capillaritis (graft accommodation-like phenotype) on 1-year biopsies of ABO-incompatible patients with and without BKVAN was 40% and 75.8%, respectively (P=0.04). Death-censored graft survival (91%) and serum creatinine level among surviving kidneys (1.8 mg/dl) were identical in ABO-and HLAincompatible patients with BKVAN (median, 1399 and 1017 days after transplantation, respectively).Conclusions ABO-incompatible kidney recipients are at greater risk for BKVAN than HLA-incompatible kidney recipients. ABO-incompatible recipients not showing the typical graft accommodation-like phenotype may be at heightened risk for BKVAN, but this observation requires replication among other groups.
A correlation between indirect allorecognition of mismatched donor HLA class I peptides and development of bronchiolitis obliterans syndrome (BOS) after lung transplantation has been previously observed. The aim of this study was to determine whether there was a correlation between indirect allorecognition of mismatched donor HLA class II peptides and development of BOS after lung transplantation. Peripheral blood mononuclear cells from nine BOSπ and nine BOSlung transplant recipients were cultured with synthetic peptides corresponding to the b-chain hypervariable region of a mismatched donor HLA-DR molecule. Then, proliferative alloreactivity as well as frequency of alloreactive T cells were determined. In addition, the immunodominant epitopes from the donor HLA-DR molecules were identified in selected patients. T cells from BOSπ patients showed a dose-dependent proliferative alloreactivity against donor HLA-DR peptides that was significantly higher than that observed in BOS-patients (pΩ0.001). Similarly, the frequency of HLA-DR alloreactive T cells was significantly higher in BOSπ patients than in BOS-patients (pΩ0.001). This T-cell alloreactivity was directed against a single immunodominant HLA-DR peptide. These results suggest that indirect alloreactivity to donor HLA class II molecules may play a role in the pathogenesis of BOS after lung transplantation.
OBJECTIVE-Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against -cells are unclear, forming the rationale for this investigation.RESEARCH DESIGN AND METHODS-A form of antilymphocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes.RESULTS-We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4 ϩ CD25 ϩ regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo.CONCLUSIONS-These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells. Diabetes 57: [405][406][407][408][409][410][411][412][413][414] 2008
Cinacalcet, a calcimimetic, was evaluated in persistent hyperparathyroidism after kidney transplantation (Tx). Ten kidney transplant recipients and one kidney-pancreas recipient with persistent post-Tx hypercalcemia (serum calcium [SCa] > 10.2 mg/dl), stable graft function, and intact parathyroid hormone (iPTH) >2 times normal received 30 mg/d cinacalcet between 2 mo and 5 yr after Tx. SCa, serum phosphorus (SP), and iPTH were measured before and after cinacalcet. Mean pre-cinacalcet SCa was 10.9 mg/dl (8.6 to 11.9 mg/dl). Average pre-cinacalcet SP was 2.9 mg/dl (1.8 to 4.0 mg/dl). Mean pre-cinacalcet iPTH was 267.0 pg/ml (99 to 723 pg/ml). After cinacalcet, SCa decreased on average by 1.6 mg/dl (95% confidence interval 1.2 to 2.1; P < 0.0001). Post-cinacalcet SP increased on average 0.45 mg/dl (P ؍ 0.046). Post-cinacalcet iPTH averaged 156.9 mg/dl (P ؍ 0.10). Graft function remained stable. Cinacalcet lowers SCa and raises SP in the short term in patients with persistent post-Tx hyperparathyroidism; long-term bone effects and persistent hyperparathyroidism merit further study.Clin J Am Soc Nephrol 1: 323-326, 2006323-326, . doi: 10.2215 H ypercalcemia is a frequent complication that ensues after successful kidney transplantation (KTx) (1). Persistent hyperparathyroidism (HPT) is the most frequent cause of post-KTx hypercalcemia (1). The usual management of hypercalcemia after KTx involves a period of conservative management followed by parathyroidectomy in cases with unremitting hypercalcemia Ͼ6 to 12 mo after KTx (1). In recent years, intravenous vitamin D 3 and other vitamin D analogs have been used in dialysis patients to suppress parathyroid hormone (PTH) levels (2). After successful KTx, these agents are discontinued abruptly, followed by an increase in PTH levels, a change in the known natural history of HPT attendant to renal failure. Recently, the calcimimetic agent cinacalcet was approved to treat the HPT that accompanies renal failure (3,4). We hypothesized that cinacalcet may be effective in lowering serum calcium (SCa) and PTH levels in some patients with persistent post-KTx hypercalcemia. We report herein our experience with cinacalcet in the management of persistent HPT and hypercalcemia after KTx. We also compare and contrast our experience with the recently published experience of two other groups that have used cinacalcet in a similar manner (5,6). Materials and MethodsThis study is a retrospective review of the clinical experience with cinacalcet at the University of Florida Kidney Transplant Program. Ten KTx patients (nine deceased donor, two living donor; six male, five female) and one simultaneous kidney-pancreas Tx patient with stable renal allograft function and persistent hypercalcemia after KTx (SCa Ͼ10.2 mg/dl), intact PTH (iPTH) greater than twice the upper limit of normal and stable graft function were started on a single daily oral dose of 30 mg cinacalcet. Cinacalcet was started between 2 mo and 5 yr (median 3 yr) after KTx. We measured SCa, phosphorus (P), and iPTH before and...
We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-γ, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-γ production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance. See related Commentary on pages 797-798rats undergoing acute vascularized allograft rejection express a restricted TCR Vβ repertoire and transfer DTH responses in vivo (16). In this study, we compared for the first time, to our knowledge, the functions of self-restricted alloreactive T-cell clones generated from grafts of rejecting and tolerant animals and analyzed the putative regulatory functions of Th2 clones in vitro and in vivo. Results of a pilot study in kidney transplant recipients with chronic rejection or stable graft function establish the biological relevance of our animal studies in humans. Our results confirm the regulatory functions of alloreactive Th2 clones and provide an invaluable tool for the study of the functions of Th1 and Th2 clones in acute/chronic allograft rejection and tolerance in vivo. MethodsAnimals. Inbred 200-250 g male Lewis (LEW; RT1 l ) rats were used as recipients and Wistar Furth (WF; RT1 u ) rats served as donors. They were purchased from Harlan Sprague-Dawley Inc. (Indianapolis, Indiana, USA).Rat kidney transplantation. LEW rats underwent bilateral nephrectomies and received heterotopic MHCincompatible WF renal allografts. For the purpose of this study, we used two groups of animals. The first group was unmodified and the rejecting graft was harvested on day 7. The second group was treated with a single injection of human cytotoxic lymphocyte activation factor 4 (CTLA4Ig; Bristol Myers Squibb Co., Princeton, New Jersey, USA) on day 2 after transplant and the graft was harvested after 100 days. This protocol of CTLA4Ig administration has previously been shown by Sayegh's group to induce long-term a...
Although patients with end-stage renal disease can be maintained with dialysis therapy, the superiority of patient survival with renal transplantation makes transplantation the preferred method of renal replacement. Potent immunosuppressive therapies, particularly calcineurin inhibitors, have greatly reduced the incidence of acute rejection. However, long-term allograft survival remains limited. We discuss the impact of acute rejection on long-term allograft survival and discuss other factors leading to late allograft loss, including calcineurin inhibitor toxicity, chronic allograft nephropathy, and BK virus nephropathy, as well as donor and recipient factors associated with long-term allograft loss.
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