Alloantibody and Intragraft Cellular Response to MHC Class I-Disparate Kidney Allografts in Recipients Tolerized by Donor-Specific Transfusion and Cyclosporine1

Abstract

Congenic PVG.RT1u rats rapidly reject Aa class I-disparate kidney allografts from recombinant PVG R8 donors and we recently demonstrated that anti-class I MHC alloantibody plays a critical role in effecting acute rejection in this experimental model. In this article, we show that PVG.RT1u recipients can be rendered permanently and specifically tolerant to R8 kidney allografts by administration of four weekly donor-specific transfusions (DST) combined with a 7-day course of cyclosporine given with the first DST. Tolerance induction correlated with abrogation of a cytotoxic alloantibody response by thymus-independent, i.e., peripheral mechanisms; IgM and all IgG subclasses of anti-class I alloantibody were abolished. In contrast, nonrejecting kidney allografts in tolerant rats and rejecting grafts from unmodified recipients were similarly infiltrated by mononuclear cells, and intragraft transcripts for interleukin (IL)-2, interferon-gamma, and IL-13 were readily detected by reverse transcriptase polymerase chain reaction with no apparent quantitative difference between the two groups. Messenger RNA for IL-4 and IL-10 was present in rejecting grafts but barely detectable in grafts from tolerant animals. These results suggest that tolerance induction by DST and cyclosporine is, in this experimental model, associated with a selective impairment in humoral alloimmunity.

Specific B Cell Tolerance Is Induced by Cyclosporin A Plus Donor-Specific Blood Transfusion Pretreatment: Prolonged Survival of MHC Class I Disparate Cardiac Allografts

“…1), and 50% of the R8 heart allografts survived indefinitely. Others showed that pretreating rats with CsA alone had no effect on allograft survival (23). A single injection of R8 blood 2 wk before transplantation and in the absence of CsA had, as expected (2), the opposite effect, inducing accelerated rejection ( Fig.…”

“…Previous studies showed that, in those donor/recipient combinations where primary allograft rejection was mediated by alloantibody, giving recipients a prior blood transfusion sensitized rather than tolerized the recipients (2,15,16,23). As a result, subsequent transplants underwent accelerated destruction.…”

“…In a well-characterized experimental model, it was shown that anti-MHC class I alloantibody was directly responsible for acute rejection of class I mismatched kidneys, hearts, and skin in the high responder PVG.RT1 u (RT1 u ) rat strain (2,14,16). In an attempt to prolong survival of MHC-mismatched organ allografts in this RT1 u strain, recipients were given a preoperative donor-specific blood transfusion (DST) (16,23), a procedure that has been used successfully in both clinical and experimental settings (24 -29). However, rather than inducing allograft acceptance, DST sensitized the recipients, resulting in production of anti-class I alloantibody and accelerated rejection (16,23).…”

“…In an attempt to prolong survival of MHC-mismatched organ allografts in this RT1 u strain, recipients were given a preoperative donor-specific blood transfusion (DST) (16,23), a procedure that has been used successfully in both clinical and experimental settings (24 -29). However, rather than inducing allograft acceptance, DST sensitized the recipients, resulting in production of anti-class I alloantibody and accelerated rejection (16,23). Bradley and colleagues (23) went on to show that the hyperacute rejection of class I-mismatched kidney allografts could be prevented and a state of unresponsiveness induced by combining the preoperative blood transfusion with a short course of CsA.…”

“…rats were purchased from Harlan Olac (Bicester, U.K.). Using a previously described protocol (23,30), euthymic RT1 u DST rats were transfused i.v. with 1.0 ml of freshly collected, heparinized donor blood from R8 strain rats syngeneic with the heart allograft or from third party PVG donors.…”