Lyme disease is currently the most prevalent vector-borne illness in the US with over 50,000 reported cases since 1977. It is caused by the spirochete Borrelia burgdorferi (Bb) and is transmitted to humans and animals by infected Ixodes ticks. Because current methods for control (including vector and reservoir reduction) are inadequate, alternative disease prevention strategies are needed. While immunization is one possible approach, many aspects of the basic immunobiology of this infection are still not well understood. Because T lymphocytes are critical participants in the developing immune response and because their role in Bb infections has not been adequately studied, we propose here a set of experiments whose common goal is to more clearly define the role(s) that T cells play in anti-Bb immunity. In previous studies, it was shown that H2/d haplotype mice (e.g. BALB/c or CB.17) are resistant to high challenge doses of Bb and develop little or no visible arthritis, whereas immunoincompetent scid mice of the H2/d haplotype are highly susceptible and develop severe arthritis (LA). The ability of this easily quantifiable endpoint (arthritis) to distinguish clinically immune from non-immune hosts provides an ideal model system for examining the immunological requirements for protection against Bb infection. We present here data from transfer studies in scid mice that effectively implicate non-antibody-dependent protective mechanisms in control of Bb infections (3B. Preliminary results, Figure 4). Furthermore, we present additional evidence from T cell subset-depletion experiments that implicate the CD4+ T cell subset in protection and the CD8+ T cell subset in disease enhancement/progression (3C. Preliminary results, Figure 5). This latter result is especially intriguing as it suggests the possibility that outcome in Bb-infected hosts is strongly influenced by the relative state of balance achieved between functionally antagonistic CD4+ and CD8+ T cell compartments. Using both in vivo and in vitro approaches, we propose here to confirm and extend these preliminary studies and particularly, to determine if patterns of cytokine production in lymphoid organs or joints of Bb-infected mice correlate with outcomes. If patterns of cytokine production are found to correlate with outcome in Bb-infected mice, we will attempt to modulate outcomes in vivo by the administration of cytokine-specific monoclonal antibodies. These studies will provide important new information concerning the role of T cells and T cell-derived cytokines in determining outcome in Bb- infected hosts and will contribute significantly to our knowledge of protective immune mechanisms and pathology.
