The role of the CD40 pathway in alloantigen-induced hyporesponsiveness in vivo.
Resting B (rB) cells are known to be incompetent APCs in vitro, which alone can induce specific unresponsiveness to single minor histocompatibility (miH) Ags and, when combined with CD40 pathway blockade, can induce hyporesponsiveness to MHC molecules in vivo. Here we show that anti-CD40 ligand (CD40L) mAb does not prevent the expression of B7-2 on allogeneic rB cells in vivo but did prolong donor-specific cardiac allograft survival. Moreover, pretreatment with professional APCs combined with anti-CD40L mAb induced hyporesponsiveness to alloantigens in vivo. rB cells from CD40 knockout mice were unable to induce unresponsiveness, while graft prolongation was achieved in CD40L knockout recipients pretreated with wild-type rB cells. These data suggest that CD40-CD40L interactions in the recipient play a critical role in the induction of hyporesponsiveness to alloantigens in vivo and that the effect of the CD40 pathway may be independent of its effect on the B7 costimulatory pathway.
Niimi
M
M
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, United Kingdom.
Pearson
T C
TC
Larsen
C P
CP
Alexander
D Z
DZ
Hollenbaugh
D
D
Aruffo
A
A
Linsley
P S
PS
Thomas
E
E
Campbell
K
K
Fanslow
W C
WC
Geha
R S
RS
Morris
P J
PJ
Wood
K J
KJ
D000069594:Abatacept; D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000637:transplantation; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D018796:Immunoconjugates; D016130:Immunophenotyping; D007275:Injections, Intravenous; D007399:Interphase / Q000276:immunology; D007519:Isoantigens / Q000008:administration & dosage / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007519:Isoantigens; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand; D000069594:Abatacept