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 proliferative responses. The frequency of donor TDL and splenocytes that expressed the Th1 cytokines IL-2, IL-12 p40, and IFN-gamma 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.
Blazar
B R
BR
Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.
Taylor
P A
PA
Panoskaltsis-Mortari
A
A
Buhlman
J
J
Xu
J
J
Flavell
R A
RA
Korngold
R
R
Noelle
R
R
Vallera
D A
DA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001667:Binding, Competitive / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D019013:CD40 Antigens / Q000187:drug effects*; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000473:pathology / Q000517:prevention & control*; D007519:Isoantigens / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D011485:Protein Binding / Q000187:drug effects
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007519:Isoantigens; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand