Heterogenous graft rejection pathways in class I major histocompatibility complex-disparate combinations and their differential susceptibility to immunomodulation induced by intravenous presensitization with relevant alloantigens.

Abstract

SummaryThe present study investigates the heterogeneity of graft rejection pathways in class I major histocompatibility complex (MHC)-disparate combinations and the susceptibility of each pathway to immunomodulation induced by intravenous presensitization with alloantigens . Depletion of CD8+ T cells was induced by repeated administration of anti-CD8 monoclonal antibody. CD8+ T cell-depleted mice failed to generate anti-allo class I MHC cytotoxic T cell (CTL) responses but exhibited anti-allo class I MHC T cell responses, such as mixed lymphocyte reaction (MLR)/ IL-2 production, that were induced by CD4+ T cells. In contrast, donor-specific intravenous presensitization (DSP), as a model of donor-specific transfusion, induced almost complete elimination of CD4+ and CD8+ T cell-mediated MLR/11,2 production, whereas this regimen did not affect the generation of CTL responses induced by DSP-resistant elements (CD8+ CTL precursors and CD4+ CTL helpers) . Prolongation of skin graft survival was not induced by either of the above two regimens alone, but by the combination of these. Prolonged graft survival was obtained irrespective of whether the administration of anti-CD8 antibody capable of eliminating CTL was started before or after DSP. The combination of DSP with injection of anti-CD4 antibody also effectively prolonged graft survival. However, this was the case only when the injection of antibody was started before DSP, because such antibody administration was capable of inhibiting the generation of CTL responses by eliminating DSP-resistant CD4+ CTL helpers. These results indicate that (a) the graft rejection in class I-disparate combinations is induced by CD8+ CTLinvolved and -independent pathways that are resistant and susceptible to DSP, respectively; (b) DSP contributes to, but is not sufficient for, the prolongation of graft survival; and (c) the suppression of graft rejection requires an additional treatment for reducing DSPresistant CTL responses . The results are discussed in the context of potential clinical application in attempts to inhibit the generation of DSP-resistant CTL responses upon the prospective DSP. mmune responses to alloantigens are initiated by the recognition of alloantigens by T helper (Th) cells . These Th cells consist of multiple subsets that differ from one another in their phenotype and mode of alloantigen recognition (1-3) . It has been shown that various subsets of Th cells initiate anti-allo-immune responses, including CTL responses, and that allograft rejection results from complicated cellular interactions, especially between T cells of different phenotypes, of different antigen-specificities, and with distinct functions (4) .The presentation of alloantigens via the intravenous route positively or negatively regulates the induction of anti-alloimmune responses as has been reported for the effect of donor-specific transfusion (DST) ' (5-15) . Earlier studies from several laboratories have demonstrated that the reduction of alloreactivity, as monitored by graft rejection resp...

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