Studies on the mechanisms by which transforming growth factor-β (TGF-β) protects against allergic encephalomyelitis: Antagonism between TGF-β 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 nervous system (CNS) capillaries and initiate inflammatory demyelinating lesions. The administration of transforming growth factor-β (TGF-β) has been shown previously to decrease the incidence and severity of EAE. In our studies we have determined: 1) the effects of TGF-β injected at different intervals after the EAE-inducing immunization; 2) the effect of TGF-β on the development of sensitized T cells, as assayed by the proliferative responses of T cells from lymph nodes and peripheral blood; 3) the extent of lymphoid cell infiltration in CNS of TGF-β-treated and control mice; and 4) the role of endogenous TGF-β and TNF in determining the severity of both acute and relapsing EAE. The onset of acute-EAE in SJL mice, induced by immunization with spinal cord homogenate in CFA and pertussigen, is on days 10 to 15. Although daily i.p. injections of 0.2 to 2 μg TGF-β₁ or TGF-β₂ 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-β accelerates and 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 protection as does TGF-β. Similarly, in relapsing EAE, anti-TGF-β increases, whereas anti-TNF decreases the incidence and severity of relapses. TGF-β treatment on days 5 to 9 does not influence the appearance of sensitized cells in peripheral blood and lymph nodes, but does prevent 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-β is exerted at the level of the target organ, CNS and/or its vascular endothelium, rather than through a direct effect on lymphoid cells, and that there is a small window of 4 days in which TGF-β exerts its protective effect.