Publications

The diverse response of individuals within populations to infectious pathogens remains poorly understood, although genetic determinants undoubtedly contribute in substantial ways to the outcome of infection. In a mouse model of infection with the intramacrophage protozoan Leishmania major, susceptibility correlates both with aberrant helper T cell differentiation biased towards the production of interleukin 4 and with the presence of an endogenous CD4 T cell repertoire that recognizes an immunodominant parasite antigen with high frequency. In the setting of the particular ecological niche occupied by Leishmania, this combination of otherwise unrelated factors synergizes to result in exquisite susceptibility to this single pathogen, without seemingly compromising host defenses against other agents. Similar paradigms could underlie susceptibility to other pathogenic organisms.

The costimulatory interaction between CD28 on T cells and B7-related molecules on antigen presenting cells plays an important role in a broad range of functions of the immune system, including protective immunity, tolerance induction, allograft rejection, and the development of autoimmune diseases. Monoclonal antibodies to B7-1 and B7-2 have been used in vivo to examine the mechanisms underlying these processes and to evaluate costimulation antagonism as an approach to treatment of chronic autoimmune diseases. To determine whether anti-B7 mAb might elicit, or inhibit, a host immune response that could influence the effects of these antibodies in vivo, we assessed the immune response to rat anti-B7-1 and anti-B7-2 mAb in healthy (BALB/c) mice and in lupus-prone NZB/NZW F1(B/W) mice. In BALB/c mice, low doses (1-10 microg) of mAb to B7-1 and mAb to B7-2 elicited brisk immune responses that occurred earlier and were significantly greater than the immune response to an isotype-matched control rat mAb to ovalbumin. In contrast, at higher doses (100-500 microg), both anti-B7 mAb, but not the control mAb, blocked the mouse anti-rat response. No such blockade occurred in B/W mice, who generated a significant mouse anti-rat response even at very high doses of anti-B7 mAb (1,000-4,000 microg). Blockade of the immune response to the anti-B7 mAb in BALB/c mice apparently did not reflect generalized immune suppression, because high doses of these mAb had little, if any effect on the humoral immune response to another antigen. These findings indicate that: (1) mAb to B7-1 and B7-2 can elicit either a potent immune response or no immune response at all depending upon the dose administered; (2) blockade of the immune response to anti-B7 mAb may be more difficult in the setting of autoimmunity; and (3) neither anti-B7-1 nor anti-B7-2 causes generalized suppression of humoral immunity.