Autoimmunity

Edited by: Thomas W. Durso V.K. Kuchroo, M.P. Das, J.A. Brown, A.M. Ranger, S.S. Zamvil, R.A. Sobel, H.L. Weiner, N. Nabavi, L.H. Glimcher, "B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy," Cell, 80:707-18, 1995. (Cited in nearly 260 publications as of April 1997) GOOD AND BAD: Harvard's Laurie Glimcher received a surprise after injecting a pair of antibodies into mice suffering from experimental allergic encephalomyelitis Comments by Laurie H. Glimcher, department of cancer biology, Harvard Medical School Costimulatory molecules called B7-1 and B7-2 activate a pair of pathways, Th1 and Th2, along which the immune system's T helper (Th) cells mature (G.J. Freeman et al., Journal of Experimental Medicine, 174:625-31, 1991; G.J. Freeman et al., Science, 262:907-9, 1993; G.J. Freeman et al., Science, 262:909-11, 1993). The discovery of B7-1 and B7-2 led to a variety of studies on their role in preventing diseases. Among them was research on tumors that showed that the presence of B7-1 increased tumor rejection. That caused Laurie H. Glimcher, the Irene Heinz Given Professor of Immunology and a professor of medicine in Harvard Medical School's department of cancer biology, and her team to examine the role of B7-1 and B7-2 in an autoimmune disease called experimental allergic encephalomyelitis (EAE). "We thought, if you can increase the immune response and increase tumor rejection by enhancing costimulatory ligand expression, then blocking it should be helpful in autoimmune disease," she recalls. Glimcher and Vijay K. Kuchroo of Harvard Medical School's department of neurology and the Center for Neurological Diseases at Brigham and Women's Hospital in Boston speculated that injecting mice suffering from EAE with antibodies to either B7-1 or B7-2 "would result in amelioration of the symptoms of paralysis. This disease is thought to be mediated by the T helper 1 cell. . . . We were thinking that if we blocked the immune response, we would make the disease better." They found that the antibody to B7-1, as expected, either cured the mice or greatly reduced their symptoms. However, much to the researchers' surprise, the mice injected with the B7-2 antibody experienced more severe symptoms. "The mice were developing paralysis early," Glimcher says. "They were dying in the cage." Further experiments produced similar results when the cytokines of the mice's cells were cultured in vitro: B7-1 antibodies increased Th1 cytokines, while B7-2 antibodies "wiped out" Th2 cytokines. The results, according to Glimcher, have caused something of an uproar. Some scientists argue that the results depended not on which costimulatory molecule was present, but on other factors, such as the signaling strengths or timing of expression of the molecules at various stages of the disease. "People were saying our interpretation was wrong, but they were repeating our experiments and getting similar results," Glimcher states. "There's a controversy in the field now as to the role of these costimulatory molecules in affecting T helper cell differentiation." Glimcher believes that the controversy has "in part" played a role in this paper's large number of citations. She adds: "It was a very new idea-that the costimulatory molecules also shape T-cell subset development, which has emerged as such an important field today." Since this paper was published, Glimcher and others illustrated that the B7-2 antibody fought off a parasite called Leishmania major by nullifying Th2 differentiation in a Th2-dominated mouse (J.A. Brown et al., Journal of Infectious Diseases, 174:1303-8, 1996). She also helped to show that the interaction between Th precursor cells and B7-2 favors the development of Th2 cells (A.M. Ranger et al., International Immunology, 8:1549-60, 1996).

Autoimmunity

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