Background: Various studies indicate the requirements for tolerance induction may vary between different transplanted tissues and organs. Consequently, we compared the efficacy of anti-leukocyte function-associated antigen-1 (LFA-1)/anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody therapy for facilitating cardiac vs islet long-term allograft acceptance in mice.
Methods: BALB/c (H-2d) mouse cardiac or islet allografts were transplanted into recipient CBA/J (H-2k) mice. Monoclonal anti-body therapy with anti-LFA-1, anti-ICAM-1, the combination, or control rat immunoglobulin (Ig) was administered intraperitoneally on Days 0 to 5. Cardiac allograft function was assessed by palpation and islet graft function by blood glucose monitoring. Mixed lymphocyte assays were performed to assess proliferation of CD4 and CD8 T-cells under conditions of stimulator-cell ICAM-1 and/or LFA-1 deficiency.
Results: Anti-ICAM-1 therapy resulted in a modest prolongation of cardiac allografts but in pronounced survival of islet allografts. Anti-LFA-1 therapy promoted significant long-term survival of both cardiac and islet allografts. Surprisingly, combined anti-LFA-1/anti-ICAM-1 therapy abrogated long-term islet, but not cardiac, allograft acceptance relative to either monotherapy. Mixed lymphocyte reactions demonstrated complete blockade of CD4 and CD8 T-cell proliferation under conditions of ICAM-1 deficiency alone or in combination with anti-LFA-1 therapy.
Conclusion: These results indicate that optimal therapies for some allografts (vascularized-heart) may not translate to other types of allografts (cellular-islet). Thus, the type of transplant represents an independent variable for optimizing strategies to promote indefinite allograft acceptance. Complete inhibition of CD4 and CD8 T-cell proliferation during ICAM-1/LFA-1 blockade suggests a threshold signal may be dependent upon ICAM-1/LFA-1 for regulatory tolerance to occur and that this signal may be lost under conditions of minimal graft cellular mass.