Gautam, Anand Mushesh; (1990) Antigen presentation in experimental autoimmune encephalomyelitis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In Lewis rats, experimental autoimmune encephalomyelitis (EAE), an inflammatory disease of the central nervous system ( CNS) with minimal demyelination, is initiated by myelin basic protein (MBP)-specific T cells, recognising MBP associated with MHC class II molecules (Ia) on the surface of antigen presenting cells (APC). An experimental system has been developed using APC preparations, enriched with macrophages (MO) or dendritic cells (DC) to compare antigen processing and presentation of the auto-antigen, rat MBP, with a foreign protein, ovalbumin (OVA). Mter incubation with antigen-pulsed APC, T cell activation was assessed by either lymphoproliferation of MBP- or OVA-sensitized lymph node cells or cellular transfer of EAE in the case of MBP-sensitized splenocytes. MBP-sensitized lymph node cells from Lewis rats were stimulated by DC, but not by MO, pulsed with MBP. In contrast, OVA-sensitized lymphocytes did not respond to OVA-pulsed DC unless the protein was first processed by macrophages. Antigenic activity in macrophage-processed OVA eluted from Sephadex G75 at apparent molecular weights of about 43 kDa and 1.5 kDa. These results suggest a need for co-operation between MO (highly phagocytic and Ia˙) and DC (less phagocytic and Ia+) in the presentation of OVA, but not for MBP. Pulsing DC simultaneously with MBP and processed OVA at a molar ratio of 1:2.5 and 1:20, progressively inhibited the ability of DC to activate MBP-specific T cells for EAE transfer. Unprocessed ovalbumin, which cannot be presented immunologically by DC, was much less effective. OVA also blocked the active induction of EAE when mixed with MBP in the sensitizing inoculum. Thus, MBP and OVA can compete for binding to Ia on Lewis rat APC both in vitro and in vivo. Initiation of EAE requires presentation of endogenous MBP by APC within the target organ, ie, the CNS. Accordingly, attempts were made to suppress EAE in the recipients of MBP-activated splenocytes by intra-cerebroventricular (icv) injections of OVA and preliminary data show that EAE was suppressed. Finally, cellular transfer of MBP-activated splenocytes into rats immunized with a myelin glycoprotein fraction was used to develop a new model of EAE with substantial demyelination to relate it more closely with the human demyelinating disease multiple sclerosis.

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