MURINE MODEL OF CUTANEOUS LYMPHOID HYPERPLASIA

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Cutaneous lymphoid hyperplasia (CLH) is a chronic inflammatory response to foreign antigens such as arthropod stings. Although the density of lymphoid infiltration can vary, in its most florid form CLH is characterized by a recapitulation of lymphoid tissue in the skin. Our studies have shown that the cellular composition and immunoarchitectural features of human CLH mimic those of reactive lymphoid tissues. Furthermore, we have shown that human CLH represents the benign end of a continuum of B-cell lymphoproliferative disorders with cutaneous B- cell lymphoma (CBCL) at its malignant extreme. An intermediate condition known as "clonal CLH" was first recognized by us and was shown to be a transitional state capable of eventuating in overt CBCL. Approximately 20 years ago, a murine model of CLH was identified during toxicological studies of insect venoms. Our preliminary data demonstrate the feasibility of reproducing this model. In this proposal, our principal aims are to refine this murine CLH model and determine if it can be driven to clonal CLH or CBCL. We will characterize its histopathology, immunoarchitectural features, clonality, and T-cell receptor and immunoglobulin gene V-region repertoires. This will form the basis of a subsequent application for long-term funding aimed at the identification of antigens and MHC restriction relevant to the CLH response, pathogenetic mechanisms of CLH and CBCL, inhibition of CLH and chemoprevention of CBCL. Because the lymphoid hyperplasia-lymphoma continuum exists in many organ systems besides the skin, analysis of the CLH-CBCL spectrum is likely not only to advance our knowledge of these skin diseases but also to improve our understanding of the general relationship between reactive and neoplastic B-cell disorders in other organ systems. We will also gain new insights into lymphoid tissue ontogeny. This project is a significant departure from our previously funded work because it deals with non-human disease and the creation of a specific animal model. In addition, it focuses primarily on B-cell disease while our prior focus has been mainly on T-cell disease. Therefore, it necessitates a major redirection and retooling of research efforts.