OX40 (CD134) blockade inhibits the co-stimulatory cascade and promotes heart allograft survival.
BACKGROUND
CD134 (OX40) is a member of the tumor necrosis factor receptor superfamily that is expressed as a late event in T-cell activation and contributes to the generation of immunologic memory. CD134 blockade effectively ameliorates inflammation in models of autoimmune disease, but its role in transplantation has been less well studied.


METHODS
The authors used an OX40-immunoglobulin (Ig) fusion protein to examine the contribution of this co-stimulatory molecule to the in vitro alloimmune response and studied the ability of CD134 blockade to prevent cardiac allograft rejection in mouse models of heart transplantation using strains representing both major histocompatibility complex (MHC) (BALB/c to CBA/Ca) and minor histocompatibility complex (mHC) (B10.BR to CBA/Ca) antigen mismatches.


RESULTS
CD134 upregulation on in vitro alloactivated T cells was delayed compared with CD69 and CD25, and inhibition of T-cell proliferation was critically dependent on the timing of OX40-Ig administration. Heart allograft survival in a fully allogeneic, MHC-mismatched strain combination was not influenced by CD134 blockade alone, but OX40-Ig treatment in the mHC-mismatched model resulted in long-term graft survival (median survival time extended from 14 days to >100 days). Early mononuclear cell infiltration of the graft was similar in both rejecting and long-surviving heart grafts, but OX40-Ig treatment appeared to delay cellular infiltration.


CONCLUSIONS
These results show that CD134-CD134L interaction plays an important role in the co-stimulatory cascade and that blockade of this molecular interaction may be of therapeutic value in helping to prevent allograft rejection.
Curry
Allison J
AJ
Department of Surgery, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Chikwe
Jo
J
Smith
Xin G
XG
Cai
Ming
M
Schwarz
Herbert
H
Bradley
J Andrew
JA
Bolton
Eleanor M
EM
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control; D008213:Lymphocyte Activation; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D023421:Models, Animal; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
D007136:Immunoglobulins; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505716:TNFRSF4 protein, human; C505717:Tnfrsf4 protein, mouse