INTERFERON-GAMMA, INTERLEUKIN-4 AND TRANSFORMING GROWTH-FACTOR-BETA IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS IN LEWIS RATS - DYNAMICS OF CELLULAR MESSENGER-RNA EXPRESSION IN THE CENTRAL-NERVOUS-SYSTEM AND LYMPHOID-CELLS

The potential role of certain important immunoregulatory and effector cytokines in autoimmune neuroinflammation have been studied. We have e xamined the expression of mRNA, with in situ hybridization, of interfe ron gamma (IFN-gamma), interleukin 4 (1L-4) and transforming growth fa ctor beta (TGF-beta) both in sections of spinal cords and the antigen- induced expression of these cytokines by lymphoid cells after stimulat ion with a dominant encephalitogenic peptide of MBP (MBP 63-88) during the course of actively induced experimental autoimmune encephalomyeli tis (EAE) in Lewis rats. In spinal cords, the target organ in EAE, cel ls expressing mRNA for IFN-gamma, first appeared at the onset of clini cal signs, i.e., day 10 postimmunization (p.i.), peaked at the height of disease (day 13 p.i.) and then gradually decreased concomitant with recovery. Very few IL-4 mRNA-expressing cells appeared in the spinal cord with no clear relation to clinical signs or histopathology. In co ntrast, expression of mRNA for TGF-beta did not increase until day 13 p.i., at height of the disease, shortly preceding recovery. These data are consistent with a disease upregulating role of IFN-gamma, while T GF-beta may act to limit central nervous system (CNS) inflammation. In lymphoid organs, primed MBP 63-88 reactive T cells showed an interest ing time-dependent evolution of their cytokine production in vitro. Th us, early after immunization there was a conspicuous MBP 63-88-induced production of both IFN-gamma and IL-4. Such cells may act in the init iation and promotion of the disease. Later, in the recovery phase, MBP 63-88 induced lymphoid cells to TGF-beta production. Thus, an autoant igen-specific production of TGF-beta occurred during EAE and hypotheti cally such a mechanism may serve to downregulate aggressive autoimmuni ty systemically. (c) 1995 Wiley-Liss, Inc.