RESUMO
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.
Assuntos
Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Humanos , Imunoglobulinas/uso terapêutico , Inflamação/prevenção & controle , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos CBA , Modelos Animais , Receptores OX40 , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Transplante de Pele/imunologia , Linfócitos T/imunologia , Transplante Homólogo/imunologiaRESUMO
Much effort is currently directed towards generating and evaluating agents that target the individual components of the alloimmune response, with a view to promoting allograft survival accompanied by minimum side effects. Recently, there has been considerable interest in inhibiting individual cytokine/receptor interactions since they are key elements in pathways for differentiation of immune effector cells. This article examines the utility of targeting interactions of interleukin (IL)-15 with its receptor as a strategy for disabling the T-cell activation events following recognition of foreign major and minor histocompatibility antigens. Experimental evidence suggests that interrupting IL-15/IL-15R interaction may be of therapeutic value in preventing allograft rejection.