MCAM Identifies Encephalitogenic TH17 Lymphocytes and Promotes Their Recruitment to the CNS (SC02.001)

Abstract

Objective: Our hypothesis is that MCAM plays an important role in CNS inflammation by promoting migration of aggressive autoreactive lymphocytes through the BBB into the CNS parenchyma. Background In multiple sclerosis (MS), encephalitogenic CD4 + lymphocytes require adhesion molecules to accumulate into central nervous system (CNS) lesions. Blocking of alpha4beta1 integrin reduces relapses but serious adverse events can arise because of the resulting CNS immunosuppression. Thus, we need to identify new molecules specifically involved in the recruitment through the BBB of highly inflammatory immune cell populations such as T H 17 lymphocytes. We identified expression of melanoma cell adhesion molecule (MCAM), a molecule that can interact with itself, on a subset of human effector memory CD4+ lymphocytes and on blood-brain barrier (BBB) endothelium. Design/Methods: Combination of ex vivo, in vitro and in situ studies using human and mouse material from healthy controls and from MS subjects and from the MS mouse model Experimental Autoimmune Encephalomyelitis (EAE). In vivo studies in EAE. Results: We demonstrate that MCAM is co-expressed by RORgamma + and IL-23Receptor + memory CD4 + lymphocytes, and that MCAM + lymphocytes express more IL-17, IL-22, GM-CSF and Granzyme B than MCAM neg lymphocytes. The proportion of MCAM + CD4 + lymphocytes is higher in the blood and in the CNS of patients affected by MS and in EAE animals, as compared to controls, and MCAM is strikingly up-regulated at the level of the BBB within lesions. Furthermore, MCAM + T H 17 lymphocytes migrate more efficiently than MCAM neg cells and MCAM blockade reduces T H 17 lymphocyte adhesion and transmigration across BBB-ECs in vitro. In vivo , MCAM depletion dampens the clinical and pathological severity of EAE and the infiltration of IL-17 + lymphocytes in the CNS of EAE animals. Conclusions: Our findings indicate that MCAM could serve as a biomarker for T H 17-dependent diseases and represents a valuable target for the treatment of T H 17-dependent CNS inflammation. Supported by: The MSSociety of Canada and the CIHR. Disclosure: Dr. Larochelle has nothing to disclose. Dr. Cayrol has nothing to disclose. Dr. Kebir has nothing to disclose. Dr. Lecuyer has nothing to disclose. Dr. Alvarez has nothing to disclose. Dr. Arbour has nothing to disclose. Dr. Prat has nothing to disclose.