Blockade of CD40 Ligand-CD40 Interaction Impairs CD4⁺ T Cell-Mediated Alloreactivity by Inhibiting Mature Donor T Cell Expansion and Function after Bone Marrow Transplantation

Alloreactive T cells require costimulatory signals via CD40 ligand (CD40L). The tissue-destructive properties of allogeneic CD4⁺ but not CD8⁺ T cells were inhibited by anti-CD40L mAb. Fewer CD4⁺ thoracic duct lymphocytes (TDL) were obtained in mAb-treated recipients. Kinetic studies revealed that CD4⁺ T cell expansion was reduced or delayed which may account, in part for the partial graft-vs-host disease protective effect of anti-CD40L mAb. TDL were found to have diminished anti-host- specific proliferate responses. The frequency of donor TDL and splenocytes that expressed the Th1 cytokines IL-2, IL-12 p40, and IFN-γ mRNA was markedly diminished in mAb-treated recipients, demonstrating that Th1-driven alloresponses were susceptible to CD40L targeting. Perforin mRNA-expressing T cells were undetectable in mAb-treated recipients, consistent with reduced in vivo lethality after the adoptive transfer of allogeneic CD4⁺ T cells. Similar findings were observed in both B cell-replete or -deficient recipients, indicating that allogeneic T cell expansion and priming can be sustained by a non-B cell, CD40⁺ host cell population. Mice receiving CD40L-deficient allogeneic CD4⁺ T cells had survival rates comparable to the rates of those given anti-CD40L mAb treatment. Because anti-CD40L mAb also was found to prevent host anti-donor-mediated marrow allograft rejection, in vivo blockade of CD40L-CD40 interactions may provide a highly beneficial approach to improving the outcome of allogeneic bone marrow transplantation.