Manipulation of the Th1/Th2 Cell Balance: An Approach to Treat Human Autoimmune Diseases?

Abstract

Differentiated T cells produce a restricted set of lymphokines, allowing their subdivision into two major subsets: Th1 and Th2 cells. This has lead to a new paradigm for immunoregulation based on the Th1/Th2 dichotomy. A strict compartmentalization of T cells into Th1 and Th2 is clearly an oversimplification: regulatory and effector mechanisms in the immune system encompass much more than Th1 and Th2 cells. This oversimplification is nevertheless useful to carry out experiments designed to test the paradigm. Based on results obtained in different experimental models of autoimmune diseases, the subdivision of T cells into Th1 and Th2 subsets has been extended to suggest that Th1 cells contribute to the pathogenesis of several organ-specific autoimmune diseases, whereas Th2 cells may inhibit disease development. Although more slowly and maybe less clearly, a similar dichotomy is starting to emerge in human autoimmune diseases. It will soon be possible to formally test immunointervention based on Th1/Th2 cell manipulation in clinical situations: the tools and a conceptual frame are already available. In this review we will examine two key factors affecting the Th1/Th2 balance: antigen and the role of cytokines influencing the development of Th1 and Th2 cells. The rational manipulation of these two variables may ultimately lead to an effective control of Th1 and Th2 cells potentially able to alter the natural course of human autoimmune diseases.

Polarized Development of Memory Cell-Like IFN-γ-Producing Cells in the Absence of TCR ζ-Chain

“…For example, our findings bear interesting similarities to those that show the loss of -chain in T cells associated with rheumatoid arthritis and lupus (24,26). An imbalanced activation and differentiation of Th1 cells may play important roles in the pathogenesis of several autoimmune diseases (47,48). Based on our results, one may speculate that the loss of -chain in TCR complexes of T cells found in autoimmune disease patients may predispose the patients to a proinflammatory condition and facilitate the disease progress.…”

A Live Diarrheal Vaccine Imprints a Th2 Cell Bias and Acts as an Anti-Inflammatory Vaccine

“…The participation of Th1/Th2-type cytokines in the development of organ-specific autoimmune disease has been well-documented (43,44). To determine whether the protective effects of Salmonella-CFA/I vaccination are Ag-specific, cytokine responses were measured ex vivo in lymphocytes isolated from spleens, PP, CLN, or spinal cords from vaccinated and unvaccinated mice, and pulsed in vitro with OVA, CFA/I fimbriae, or PLP 139 -151 (Fig.…”

Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis

“…Numerous studies have established IL-12 as an important factor for the differentiation of naive T cells into IFN-g-producing Th1 cells, which are essential for cell-mediated immunity, including antimicrobial responses and tumor suppression (3)(4)(5). Over the past decade, IL-12-driven Th1 cells were also shown to be essential for the induction of autoimmune diseases, primarily through investigations using IL-12p40 -/-mice and IL-12p40-neutralizing antibodies (6)(7)(8)(9)(10)(11)(12)(13). However, mice lacking certain components of the Th1/IFN-g pathway (IL-12p35 -/-, IL-12b1 -/-, IFN-g -/-, IFN-gR -/-, and STAT1; R, receptor) are highly susceptible to inflammatory autoimmune diseases, indicating that these regulatory factors are not always required for disease induction (14)(15)(16)(17)(18)(19).…”