Autoimmunity

Edited by: Thomas W. Durso D.J. Lenschow, S.C. Ho, H. Sattar, L. Rhee, G. Gray, N. Nabavi, K.C. Herold, J.A. Bluestone, "Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse," Journal of Experimental Medicine, 181:1145-55, 1995 (Cited in more than 100 papers as of April 1997) Comments by Jeffrey A. Bluestone, Ben May Institute, University of Chicago ONE OR THE OTHER: Jeffrey Bluestone of the University of Chicago helped discover which of two costimulatory molecules is important in the progression of autoimmune diabetes. While Harvard Medical School's Laurie H. Glimcher was examining the role of the costimulatory molecules B7-1 and B7-2 in experimental allergic encephalomyelitis (EAE), Jeffrey A. Bluestone was studying their role in autoimmune diabetes. B7-1 and B7-2 activate a pair of pathways, Th1 and Th2, along which the immune system's T helper (Th) cells mature. Bluestone, the Charles B. Huggins Professor and director of the Ben May Institute for Cancer Research at the University of Chicago, derived some interesting results. "The basic conclusions of the study were that, indeed, [B7-1 and B7-2] played a critical role in the development of the disease [and] that B7-2 was in fact the dominant costimulatory molecule that was essential for disease progression," he reports. "The major surprise was that the treatment of the mice with anti-B7-1 monoclonal antibodies gave an unexpected opposite result. It resulted in exacerbation of the disease." This was unexpected because in Glimcher's study (V.K. Kuchroo et al., Cell, 80:707-18, 1995; Hot Papers, The Scientist, May 26, 1997, page 12), it was B7-1 that eased symptoms of EAE and B7-2 that made the disease worse. Asked why he thinks his paper has been highly cited, Bluestone replies: "It emphasized for the first time two things: the critical importance of this pathway in the development and progression of a spontaneous autoimmune disease; and second, these two ligands for the same family of molecules could have opposite effects or functions within the immune system depending on the treatment course. "Together the papers have emphasized the critical importance of the temporal expression of these two molecules, that both can vary during an autoimmune response and in different disease settings. It emphasized the complexity of their function. Depending on when and where they're expressed, the CD28/CTLA-4 ligands, B7-1 and B7-2, can have quite distinct functions." More recently, Bluestone and his team demonstrated that a B7-2 blockade is effective only "during a fairly small window," at five to seven weeks, in diabetes's progression (D.J. Lenschow et al., Annual Review of Immunology, 14:233-58, 1996). "In fact, a blockade of CD28/B7 interactions early on in the disease makes the disease much worse," he explains. "In our hands, this really comes down to where and when, as opposed to what is being affected." While Glimcher's paper attributed the different effects to the specific antibody-either B7-1 or B7-2-Bluestone offers another explanation (D. Lenschow et al., Immunity, 5:285-93, 1996; I.C. Rulifson et al., Journal of Immunology, 158:658-65, 1997). He contends that "it really isn't solely the intrinsic activities of the two molecules, but the overall strength of interaction and signaling through [them]. We can skew toward Th1 or Th2 based on when we do the treatment and in what milieu. . . . There's a really strong feeling now in the community that this pathway is absolutely critical in the development and progression of immune response, because it regulates cell survival and cell expansion. "That's not to say that one molecule might not be better at inducing Th response, but it supports that when and where these molecules are expressed are as important as which one is expressed."

Autoimmunity

The Scientist Staff

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