H.influenzae type b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis are serious pathogens for young children and immunocompromised adults. Predisposing conditions include malignancy, acute and chronic leukemias, Hodgkin's disease, and bone marrow transplant patients. In addition, we have recently described selective immunodeficiencies for these pathogens. The major risk factor for each of these groups of patients is impaired immune response to the capsular polysaccharide (Ps) antigens. Although linking the Ps to proteins (i.e., conjugate vaccines) has greatly improved immunogenicity in older normal children, immunocompromised patients are still at risk. Thus, further understanding of the Ps immune response is of great importance to many patient groups. We propose to study the human in vitro immune response to Ps. We plan to examine the phenotype of B cells responding to Ps, the structural and cellular requirements for Ps activation of B cells, and the role of C3d in Ps activation. Finally, we will study the effect of T cell lymphokines on the Ps activated B cells. To complement the human in vitro work, we plan to study murine Ps responses in vivo. We will focus on the role of T cells and T cell lymphokines on Ps specific responses. Previous studies have had to rely on incomplete and flawed models of T cell depletions. We will employ newly available T cell deficient transgenic mice as well as mice with severe combined immunodeficiency. These murine models will allow us to study the role of specific T cells (CD4, CD8, gamma/delta cells) in the immune response and the ontogeny of response to Ps antigens. Finally, we have developed murine models to evaluate the role of IL-4 and IFN-gamma on antigen specific responses. We will examine the effects of these lymphokines on the subclass specific response to Ps antigens. In summary, we propose to study both in vitro and in vivo B cell and T cell responses to Ps antigens. This work has significance for understanding the impaired responses of many immunocompromised patients. In addition to identifying such patients, new preventive strategies may result from defining the mechanisms involved.
