RESUMO
BACKGROUND: CTLA-4 immunoglobulin fusion proteins (CTLA4-Ig) suppress immune reactions by blocking the T-cell costimulatory CD28-CD80-86 pathway and are used in clinical trials for diseases featuring exaggerated T-cell reactivity including autoimmune diseases and allograft rejection. However, because CTLA4-Ig has been suspected to interfere with T regulatory (Treg) cell homeostasis and function, recently, substantial concerns on CTLA4-Ig's potentially antitolerogenic effects have been raised. METHODS: We tested immunoregulatory CTLA4-Ig explicitly for its effect on Treg cell numbers, frequencies and function in an in vitro murine major histocompatibility complex mismatched setting using C57BL/6 bone marrow-derived dendritic cells as stimulators of allogeneic Balb/c Foxp3 T cells, which allowed for tracing Treg cells in a straightforward fashion. RESULTS: The presence of CTLA4-Ig in mixed leukocyte reactions-while dampening the global proliferative response of allostimulated Balb/c T cells-resulted in a relative increase of the frequency of thymus-derived CD4CD25Foxp3 Treg cells with intact suppressive activity. This relative increase was caused by a selective inhibitory effect of CTLA4-Ig on proliferating conventional T cells, whereas the proliferative capacity of Treg cells in cell cultures remained unaffected. Additionally, in the presence of CTLA4-Ig, the frequency of apoptosis was decreased in these cells. CONCLUSION: Our findings unequivocally demonstrate that CTLA4-Ig does not negatively affect Treg cell frequencies and function in vitro.
Assuntos
Imunoconjugados/farmacologia , Linfócitos T Reguladores/citologia , Timo/citologia , Abatacepte , Animais , Apoptose , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Sobrevivência Celular , Feminino , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Autoantibodies to brain proteins are present in Juvenile Neuronal Ceroid Lipofuscinosis (Batten disease) patients and in the Cln3-/- mouse model of this disease, suggesting an autoimmune component to pathogenesis. Using genetic or pharmaceutical approaches to attenuate this immune response in Cln3-/- mice, we demonstrate decreased neuroinflammation, decreased deposition of immunoglobulin G in the brain and protection of vulnerable neuron populations. Moreover, immune suppression results in a significant improvement in motor performance providing for the first plausible therapeutic approach for juvenile Batten disease.
