The Role of Chemokines in AIDS-associated Lymphoma

Otoniel Martinez-Maza, UC-Los Angeles
Biomedical and Clinical Sciences

Background: The overall aim of this study is to define the role of chemokines in the pathogenesis of AIDS-associated non-Hodgkin's lymphoma, a B cell cancer that occurs commonly in HIV+ subjects. Chemokines (chemoattractant cytokines) are cytokines that direct the movement of immune cells. The specific aims of this project were to: 1) elucidate in vivo expression of chemokine receptors and related ligands in subjects who developed AIDS-lymphoma and 2) define in vivo roles for selected chemokines in AIDS-lymphoma tumor cell growth using a SCID mouse model for non-Hodgkin's lymphoma.

Methods: We have identified a number of chemokines, as well as othermolecules, as beingassociated withAIDS-lymphoma. This study was done using archival plasma from the Multicenter AIDS Cohort Study (MACS) at UCLA. The MACS is a study of the natural history of AIDS that was initiated more than 20 years ago. Subjects in the MACS are seen at two study visits per year, during which serum, plasma, and peripheral blood mononuclear cells are collected and stored. Additionally, extensive clinical and epidemiological information is collected on these study subjects. Nearly 200 subjects in the MACS have developed AIDS-lymphoma. Pre-cancer diagnosis plasma samples were obtained from MACS subjects who developed AIDS-lymphoma. Plasma also was obtained from subjects with AIDS who did not develop lymphoma. Using ELISA-type assays, we examined the expression of 17 chemokines and other markers in this plasma.
Results: Five markers showed a statistically significant elevation in the pre-lymphoma plasma, compared to the control plasma: three chemokines (CXCL13, ITAC and MIP-1 beta), a metallomatrix protein (MMP-9), and one hematopoietin-family cytokine (IL-10). Four other markers showed an elevation in those who went on to develop AIDS-lymphoma that was of borderline significance, including a chemokine (TARC) and three other molecules (ICAM-1, VCAM-1, and VEGF). Eight other markers showed no elevation pre-AIDS-lymphoma, including four chemokines (MIP-1 alpha, MIP-3 alpha, MIG, and IL-16), and four other molecules (IL-6, IL-12, sCD40L, and L-selectin). In other studies, we examined CXCR5 and CXCL13 expres-sioninAIDS-lymphoma tumors, usingimmunohistochemistry. All AIDS-NHL tumors showed some degree of CXCR5 expression, and most (22/24) expressed CXCL13.

Conclusions: We have identified a number of chemokines and other markers that are potentially associated with AIDS-lymphoma. Studies to explore the role of chemokines in vivo, in a SCID mouse model, are underway.