STUDIES ON THE MECHANISMS BY WHICH TRANSFORMING GROWTH-FACTOR-BETA (TGF-BETA) PROTECTS AGAINST ALLERGIC ENCEPHALOMYELITIS - ANTAGONISM BETWEEN TGF-BETA AND TUMOR-NECROSIS-FACTOR

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease in which peripheral lymphoid cells are activated by immunization with myelin proteins and become effector cells that traverse the central n ervous system (CNS) capillaries and initiate inflammatory demyelinatin g lesions. The administration of transforming growth factor-beta (TGF- beta) has been shown previously to decrease the incidence and severity of EAE. In our studies we have determined: 1) the effects of TGF-beta injected at different intervals after the EAE-inducing immunization; 2) the effect of TGF-beta on the development of sensitized T cells, as assayed by the proliferative responses of T cells from lymph nodes an d peripheral blood; 3) the extent of lymphoid cell infiltration in CNS of TGF-beta-treated and control mice; and 4) the role of endogenous T GF-beta and TNF in determining the severity of both acute and relapsin g EAE. The onset of acute-EAE in SJL mice, induced by immunization wit h spinal cord homogenate in CFA and pertussigen, is on days 10 to 15. Although daily i.p. injections of 0.2 to 2 mug TGF-beta1 or TGF-beta2 on days 5 to 9 after immunization are highly protective, injections on days 1 to 5 or 9 to 13 are not. Moreover, anti-TGF-beta accelerates a nd aggrevates EAE when given on days 5 and 9, but not on day 12. Anti- TNF, injected on days 5 and 9, provides a comparable degree of protect ion as does TGF-beta. Similarly, in relapsing EAE, anti-TGF-beta incre ases, whereas anti-TNF decreases the incidence and severity of relapse s. TGF-beta treatment on days 5 to 9 does not influence the appearance of sensitized cells in peripheral blood and lymph nodes, but does pre vent the accumulation of T cells in brain and spinal cord, as assayed on days 15 to 20. It is concluded that the protective effect of TGF-be ta is exerted at the level of the target organ, CNS and/or its vascula r endothelium, rather than through a direct effect on lymphoid cells, and that there is a small window of 4 days in which TGF-beta exerts it s protective effect.