The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases.

The importance of transforming growth factor-beta-1 (TGF-beta1) in immunoregulation and tolerance has been increasingly recognized. It is now proposed that there are populations of regulatory T cells (T-reg), some designated T-helper type 3 (Th3), that exert their action primarily by secreting this cytokine. Here, we emphasize the following concepts: (1) TGF-beta1 has multiple suppressive actions on T cells, B cells, macrophages, and other cells, and increased TGF-beta1 production correlates with protection and/or recovery from autoimmune diseases; (2) TGF-beta1 and CTLA-4 are molecules that work together to terminate immune responses; (3) Th0, Th1 and Th2 clones can all secrete TGF-beta1 upon cross-linking of CTLA-4 (the functional significance of this in autoimmune diseases has not been reported, but TGF-beta1-producing regulatory T-cell clones can produce type 1 inflammatory cytokines); (4) TGF-beta1 may play a role in the passage from effector to memory T cells; (5) TGF-beta1 acts with some other inhibitory molecules to maintain a state of tolerance, which is most evident in immunologically privileged sites, but may also be important in other organs; (6) TGF-beta1 is produced by many cell types, is always present in the plasma (in its latent form) and permeates all organs, binding to matrix components and creating a reservoir of this immunosuppressive molecule; and (7) TGF-beta1 downregulates adhesion molecules and inhibits adhesion of leukocytes to endothelial cells. We propose that rather than being passive targets of autoimmunity, tissues and organs actively suppress autoreactive lymphocytes. We review the beneficial effects of administering TGF-beta1 in several autoimmune diseases, and show that it can be effectively administered by a somatic gene therapy approach, which results in depressed inflammatory cytokine production and increased endogenous regulatory cytokine production. Copyright 2000 Academic Press.