Despite many years of intensive research, multiple sclerosis (MS) defies understanding and treatment remains suboptimal. The prevailing hypothesis is that MS is immune mediated and that experimental allergic encephalomyelitis (EAE) is a suitable model to elucidate pathogenesis and devise therapy. This review examines critically the validity that EAE is an adequate and useful animal model of MS and finds credible evidence lacking. EAE represents more a model of acute central nervous system inflammation than the counterpart of MS. We propose to reconsider the utilization of EAE, especially when this model is used to define therapy. This will also force us to examine MS without the restraints imposed by EAE, as to what it is, rather than what it looks like.

Experimental Allergic Encephalomyelitis: A Misleading Model of Multiple Sclerosis

Experimental and clinical data have demonstrated that activating the immune system in the CNS can be destructive. However, other studies have shown that enhancing an immune response can be therapeutic, and several clinical trials have been initiated with the aim of boosting immune responses in the CNS of individuals with spinal cord injury, multiple sclerosis and Alzheimer's disease. Here, we evaluate the controversies in the field and discuss the remaining scientific challenges that are associated with enhancing immune function in the CNS to treat neurological diseases.

Can the immune system be harnessed to repair the CNS

We previously demonstrated the feasibility of generating therapeutic numbers of cytotoxic T lymphocyte (CTL) clones expressing a CD20-specific scFvFc:CD3zeta chimeric T cell receptor (cTCR), making them specifically cytotoxic for CD20+ B lymphoma cells. However, the process of generating and expanding he CTL clones was laborious, the CTL clones expressed the cTCR at low surface density, and they exhibited suboptimal proliferation and cytotoxicity. To improve the performance of the CTLs in vitro and in vivo, we engineered "second-generation'' plasmid constructs containing a translational enhancer (SP163) and CD28 and CD137 costimulatory domains in cis with the CD3zeta intracellular signaling domain of the cTCR gene. Furthermore, we verified the superiority of generating genetically modified polyclonal T cells expressing the second-generation cTCR rather than T cell clones. Our results demonstrate that SP163 enhances the surface expression of the cTCR; that the second-generation cTCR improves CTL activation, proliferation, and cytotoxicity; and that polyclonal T cells proliferate rapidly in vitro and mediate potent CD20-specific cytotoxicity. This study provides the preclinical basis for a clinical trial of adoptive T cell immunotherapy for patients with relapsed CD20+ mantle cell lymphoma and indolent lymphomas.

Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains.

Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation.

Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes.

We demonstrate here the feasibility of antigen-specifically redirecting T cells against autoreactive T lymphocytes and thereby treating a model autoimmune disease. We created and transgenically expressed on T cells a heterodimeric chimeric receptor that genetically links an autoantigenic peptide, its restricting MHC, and the signal transduction domain of the T-cell receptor (TCR) ζ-chain. Engagement of the chimeric receptor by the TCR of autoreactive T cells activated the receptor-modified T cells in vitro and in vivo, inducing proliferation and cytolysis. Adoptively transferred receptor-modified T cells prevented and treated a model autoimmune disease, experimental allergic encephalomyelitis (EAE), even after epitope spreading had diversified the autoantigenic response. Treatment reduced disease severity and increased survival of affected animals, and was durable for >75 days. The receptor-modified cells acted both by strongly attenuating T-cell response to autoantigen as well as by shifting the residual response from an immunopathologic Th1 to a protective Th2 format.

M Divya Jyothi

Papers

Targeting autoantigen-specific T cells and suppression of autoimmune encephalomyelitis with receptor-modified T lymphocytes.