Assuntos
Toxina Diftérica/uso terapêutico , Facilitação Imunológica de Enxerto , Interleucina-2/uso terapêutico , Transplante das Ilhotas Pancreáticas , Proteínas Recombinantes/uso terapêutico , Animais , Toxina Diftérica/genética , Tolerância Imunológica , Interleucina-2/genética , Masculino , Camundongos , Camundongos Endogâmicos DBARESUMO
Allograft rejection is dependent upon complex cell-mediated processes, the primary effectors of which are activated T cells. As the expression of the cell surface protein interleukin 2 receptor is primarily limited to the subset of stimulated T cells, therapeutic agents that target this molecule may provide highly selective immunosuppression. A newly constructed chimeric IL-2 diphtheria toxin fusion protein specifically binds to and poisons activated T cells bearing the high-affinity IL-2R. We describe the in vivo effects of IL-2 toxin in preventing rejection of a crude pancreatic islet preparation transplanted across major and minor histoincompatibility barriers. IL-2 toxin administered once daily as the sole immunosuppressive agent prolongs islet graft survival and decreases the severity of the early mononuclear cell infiltrate into the graft site. Long-term survival of transplanted islets (greater than 100 days) was achieved following a short course (10 days) of more-intensive IL-2 toxin treatment. Thus IL-2 toxin, a highly selective immunosuppressive agent, leads to prolonged islet cell engraftment while sparing the resting or memory subset of the entire T cell repertoire.
Assuntos
Toxina Diftérica/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Interleucina-2/uso terapêutico , Transplante das Ilhotas Pancreáticas , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Animais , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/cirurgia , Imunossupressores/uso terapêutico , Linfócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBARESUMO
Monoclonal antibodies (Mab) targeting certain T cell-surface proteins including the interleukin-2 (IL2) receptor molecule exert powerful immunosuppressive effects. A potential limiting factor to Mab therapy is the formation of neutralizing anti-idiotypic antibodies (Anti-Id). In this study, we demonstrate that an anti-IL2 receptor Mab, M7/20, when administered at doses which are immunosuppressive in vivo rapidly elicits an anti-idiotypic (anti-Id) antibody response. The induced antibodies are capable of blocking M7/20 binding to its target, the IL2 receptor, in vitro. Such anti-Id when given in concert with M7/20 block the expected in vivo inhibitory effects in delayed type hypersensitivity. Thus, mice respond to therapeutic doses of Mab therapy with the formation of neutralizing anti-Id. As this response is similar to that observed in humans given xenogeneic Mab, this model may be useful to further our understanding of this form of therapy.