Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection.

Abstract

Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion protein which binds B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig therapy on the process of chronic renal allograft rejection using an established experimental transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition ofalloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventing development of the process.The most common cause of human allograft failure after the first year posttransplant is the incompletely understood clinicopathological entity of chronic rejection (1-3). This process affects all types of solid organ grafts and is characterized morphologically by obliterative vasculopathy, interstitial fibrosis with variable degrees of mononuclear cell infiltration, and in the case of the kidney, glomerulosclerosis. Risk factors for its development include HLA mismatching, acute rejection, early graft ischemia, differences in donor and recipient size, adequacy of immunosuppression, and viral infections. The exact mechanisms responsible for its pathogenesis are unknown, although there is evidence that chronic graft dysfunction is mediated by both alloantigendependent as well as alloantigen-independent mechanisms (4). At this moment no specific therapies are available.T-cell recognition of alloantigens is the key initial event which ultimately results in allograft rejection (5, 6). T cells require two signals for full activation. The first signal is produced by engagement of the T-cell receptor with the foreign antigen presented as a peptide by antigen-presenting cells, thus providing antigenspecificity to the immune response. The second is a "costimulatory" signal mediated, among other interactions, by the T-cell accessory molecule CD28 interacting with the B7 family (B7-1 and B7-2) of molecules on antigen-presenting cells (7-9). In vitro, blockade of costimulatory signals inhibits T-cell activation and induces a state of antigen-specific unresponsiveness. In vivo, agents which block CD28-B7 costimulation, including the fusion protein CTLA4Ig or anti-B7 monoclonal antibodies, have been shown to inhibit the immune response in experimental models of acute transplant rejection and autoimmunity (10). In this study we have investigated the role of T-cell costimulatory blockade in an established model of chronic renal allograft rejection. MATERIALS AND METHODSAnimals. Inbred 200-250 g male LEW rats (RT11) were used as graft recipients and F344 (RT1lvl) rats served as donors (Harlan-Spra...

Combined effects of calcineurin inhibitors or sirolimus with anti-CD40L mAb on alloengraftment under nonmyeloablative conditions

“…21 Another study found that CsA did not abrogate renal allograft survival facilitated by CTLA4 immunoglobulin-mediated CD28/B7 blockade. 23 Our data indicate that CsA did not abrogate donor BM engraftment mediated by anti-CD40L mAb and, under some conditions, increased the proportion of recipients that engrafted ( Table 2, experiment 2). We hypothesize that CsA reduced the intensity of TCR signaling or clonally reduced the alloreactive T-cell population that may allow for a more readily attainable costimulatory blockade in a greater proportion of recipients.…”

“…Literature reports have indicated that these immune suppressive agents can either inhibit or enhance solid organ graft acceptance when used in combination with costimulatory pathway blockade. 16,18,[20][21][22][23] In contrast to the restricted expression of alloantigen on a solid organ graft, alloantigenic targets of an immune response are widely distributed throughout the recipient or on donor BM cells that are systemically infused. In addition, patients are conditioned for BMT with chemotherapy and/or radiotherapy that can induce proinflammatory responses resulting in increased T-cell alloreactivity.…”

Donor and recipient leukocytes in organ allografts of recipients with variable donor-specific tolerance: With particular reference to chronic rejection

“…4 Although nonimmunologic factors may contribute to the immunopathological characteristics of CR, [75][76][77][78][79] evidence supporting a straightforword donor-specific HVG response as the core cause is overwhelming. [80][81][82][83][84] This pathogenesis explains very well why it has been so difficult in human organ recipients to achieve the closely related objectives of drug-free tolerance and freedom from CR. The prevention with immunosuppression of destructive immunity (i.e., rejection) for long enough to allow the variable induction of tolerance has been the sine qua non of clinical organ transplantation.…”

Adeno-Associated Virus–Mediated CTLA4Ig Gene Transfer Protects MHC-Mismatched Renal Allografts from Chronic Rejection

“…The sole possibility is to target nonimmune events, an option that works well in animals (7,18,19) but much less so in humans (20). Previous studies have found that systemic administration of the fusion protein CTLA4Ig or anti-CD28 mAb in addition to low-dose CsA to LW rat that received a Fisher kidney limited chronic rejection and prolonged survival (21)(22)(23). Inspired by these pivotal observations, we carried out this study using WF (RT1 u ) rats as donors and LW (RT1 l ) rats as recipients, which, being fully mismatched on both MHC class I and II antigens, could be representative of a broader range of clinical settings.…”