MRI-Controlled Phase I/II Trial for Treatment of Relapsing MS Using Peptide-Coupled PBL Tolerance

Principal Investigators:
Stephen D. Miller, Northwestern University, Chicago, IL

Abstract | Investigators | Background

Abstract

The objectives of this trial are to assess the safety and efficacy of treating early relapsing-remitting multiple sclerosis (RR-MS) patients using peripheral tolerance induced by the i.v. administration of autologous ethylene carbodimide (ECDI)-fixed peripheral blood lymphocytes (PBL) pulsed with multiple immunodominant myelin peptides.

MS is an autoimmune CNS demyelinating disease mediated by pro-inflammatory myelin peptide-specific CD4+ Th1 cells. Experimental autoimmune encephalomyelitis (EAE) data has clearly shown that chronic CNS demyelination involves the activation of T cell responses to multiple endogenous antigens arising via epitope spreading. MS patients also clearly react to multiple myelin epitopes and likely undergo epitope spreading. Therefore, the ideal therapy for MS would be early intervention using an antigen-specific tolerance protocol which can regulate both activated and naïve autoreactive T cells specific for multiple potential encephalitogenic epitopes.

Our preclinical experiments have shown that a single i.v. injection of ECDI-fixed naïve murine splenocytes pulsed with a mixture of encephalitogenic myelin peptides is highly efficient in inducing peptide-specific tolerance and preventing and, more relevantly, ameliorating ongoing relapsing EAE in SJL mice. This protocol induces peptide-specific tolerance in both mouse and human T cells in vitro and sustainably prevents/treats multiple in vivo animal autoimmune disease models (EAE, EAT, EAN, EAU, EAM). Thus, peripheral tolerization via injection of patient-specific autoantigenic peptides-coupled to syngeneic PBLs is a highly promising therapeutic approach that should be tested for safety and indications of efficacy in early RR-MS.

The study is an open-label, single center, baseline-to-treatment cross-over phase I/II clinical trial to assess the safety, preliminary efficacy and in vivo mechanism(s) of action of i.v. administration of 5x108 ECDI-fixed, autologous PBLs (collected by plasmapheresis) coupled with a cocktail containing five immunodominant myelin peptides (MBP111-129, MBP83-99, MBP146-170, MOG35-55, and PLP139-154) to which T cell responses are demonstrable in early RR MS patients. Immunological studies and clinical and MRI parameters will be employed to document the safety, efficacy and in vivo mechanism(s) of action. MRI and clinical studies will be conducted monthly with MRI serving as the primary clinical outcome since smaller patient groups are required and clinical outcomes are too variable to properly reflect the brain inflammatory activity during shorter trial intervals.

Mechanistic assays will be performed twice during baseline, 4 times during the treatment/trial monitoring period (7 months) and twice during a 6 month follow up. The precursor frequency (using ELISPOT, intracellular cytokine staining, and MHC II tetramers) of myelin-specific (epitopes derived from MBP, PLP, MOG, CNPase and MOBP) and recall (e.g. tetanus toxoid) antigen-specific Th1 and Th2 cells, their functional and surface marker phenotype, and naïve/memory origin will be determined by the participating labs and possibly the ITN Core Labs. Assays addressing potential mechanism(s) of in vivo tolerance will include thymidine and CFSE-based T cell proliferation assays and cytokine assays + IL-7 (to test activated vs. naïve T cells), + anti-CTLA-4 (to determine CTLA-4-dependence of tolerance) and + IL-2 (to determine if anergy is induced) and will be performed at NIH and Northwestern. Gene expression profiling will be performed using the ITN core to determine the effects of tolerance on expression of T cell transcription factors associated with Th1/Th2 activation/anergy and cell cycle genes affected by CTLA-4 signaling.

Participating Investigators

	Stephen D. Miller, Nothwestern University, Chicago, IL
	Roland M. Martin, National Institutes of Health, Bethesda, MD
	Henry F. McFarland, National Institutes of Health, Bethesda, MD

Background Articles

	The role of MRI as a surrogate outcome measure in multiple sclerosis - Mult Scler [PubMed]
	Epitope spreading in immune-mediated diseases: implications for immunotherapy - Nat Rev Immunol [go]
	Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis - J Immunol [go]