Development of autoimmunity after skin graft rejection via an indirect alloresponse

Background. T cell allorecognition occurs through direct contact with donor peptide: MHC complexes on graft cells and through indirect recognition of donorderived determinants expressed by recipient MHC molecules. As both indirect allorecognition and autoantigen recognition are self-restricted, we hypothesized that chronic activation of indirectly primed T cells might result in determinant spreading to involve autoantigens, analogous to that which occurs during chronic autoimmune diseases. Methods. We placed C57BL/6 MHC II knockout (B6 II-/-) skin grafts onto BALB/c SCID mice reconstituted with wild-type (WT) CD4⁺ T cells. Under these conditions the CD4⁺ cells could not recognize any antigen on the graft, but could respond through the indirect pathway. CD4⁺ cell-mediated rejection of WT B6 skin was studied to determine if autoreactivity was induced after direct allorecognition. Recall immune responses against donor- and self-stimulator cells were determined by ELISPOT and animals were tested for their ability to reject second isografts. Results. WT allografts were rejected by day 14 although B6 II-/- grafts underwent delayed rejection over 4-5 weeks. CD4⁺ cells reisolated from the recipients of the MHC II-/- grafts, but not from the recipients of WT grafts, vigorously produced interferon-γ and interleukin-2 in response to self, BALB/c stimulators. These autoreactive CD4⁺ T cells mediated rejection of a second isogenic BALB/c skin graft, demonstrating that the autoimmune response was pathogenic. Conclusion. Autoreactivity can develop after transplant rejection via the indirect pathway. Although the direct alloresponse is likely to be the driving force in acute graft rejection, posttransplantation induced autoimmune responses may be important elements of delayed or chronic rejection.