CTLA-4 blockade enhances t cell responses and exacerbates experimental autoimmune encephalomyelitis

Murine relapsing-remitting experimental autoimmune encephalomyelitis (REAE) is a CD4⁺ T cell-mediated demyelinating disease and serves as a model for multiple sclerosis. R-EAE is induced in SJL/J mice by immunization with the immunodominant epitope on proteolipid protein, PLP139-151, or by the adoptive transfer of T cells specific to that epitope. Activated CD4⁺ T cells have been shown to transiently express the CD28 homologue, CTLA-4, which was earlier thought to be an alternative costimulatory molecule, but has recently been proposed to serve a negative regulatory function. We investigated the role of CTLA-4 in PLP139-151-specific T cell responses and the effect of its blockade on the clinical course of R-EAE. Anti-CTLA-4 mAbs and their F(ab) fragments were used in in vitro proliferation assays and resulted in enhanced proliferation of PLP139-151-primed lymph node cells (LNC) with increased production of IL-2 and IFN-γ. Addition of anti-CTLA-4 mAbs to in vitro activation cultures of PLP139-151-specific LNC, used for the adoptive transfer of EAE, resulted in an accelerated and more severe disease course as compared to cultures to which control Ig was added. In vivo treatment of recipients of PLP139-151-specific T cells with anti-CTLA-4 also resulted in significant exacerbation of disease severity concomitant with enhanced in vivo DTH responses to PLP139-151. Lastly, administration of anti-CTLA-4 during remission after the acute phase of disease, caused exacerbation of clinical relapses. Collectively, these results indicate that CTLA-4 has a major role in downregulating established immune responses and may be responsible for controlling ongoing destruction in autoimmune settings. (Supported in part by USPHS NIH Grants NS26543 and NS34819).