Resistance to experimental autoimmune encephalomyelitis induced by neonatal tolerization to myelin basic protein: clonal elimination vs. regulation of autoaggressive lymphocytes

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Abstract
The target autoantigen of experimental autoimmune encephalomyelitis (EAE), myelin basic protein (MBP), appears late in ontogeny. In the rat MBP is expressed first on days 2–3 post partum, at a development stage, when self tolerance to most other autoantigens has already developed. To shed light on the cellular mechanisms that lead to immunological self tolerance to MBP, we treated neonatal rats with high doses of MBP before ontogenetic appearance of this autoantigen. We found that high doses are required to confer MBP-specific tolerance lasting until the adult life. Neonatally tolerized, adult rats are completely resistant to induction of EAE by injection of MBP in complete Freund's adjuvant (CFA). Upon MBP CFA challenge, these animals develop a limited humoral response to MBP, but are completely unreactive to MBP on the T cell level. The function of antigen-presenting cells is unchanged by neonatal tolerization, and there is no evidence for the induction of suppressive mechanisms. Transfers of large numbers of tolerized lymphocytes to normal hosts fails to interfere with EAE inducibility. Moreover, neonatally tolerized lymphocytes do not reduce MBP reactivity of primed lymph node cells or T line cells in vitro. Finally, neonatally tolerized rats are susceptible to EAE transferred by activated primed lymphocytes or by in vitro-activated MBP-specific T line cells. The apparent deletion of MBP-specific T lymphocytes in neonatally tolerized rats is in striking contrast to the physiological self tolerance to MBP, which is characterized by the presence of MBP-specific clones in the normal immune repertoire.