Our results have demonstrated that retinoic acid (RA) enhances the induction of plaque-forming cells from human tonsillar lymphocytes by a direct effect upon B cells. The nature of this effect may be by direct promotion of B-cell maturation or, alternatively, by the ability of RA to alter the sensitivity of B cells to regulatory cells involved in maturational processes. We will address these possibilities by testing for RA-induced changes in the sensitivity of purified B-cell populations to the regulatory activity of the known T-helper and T-suppressor cells in this system, i.e., T(mu) and T(gamma) cells, respectively. We will also test for the ability of RA to influence directly the maturation of B-leukemic populations. RA-induced changes will be evaluated by morphologic criteria and alterations in antibody secretion. Our studies to date have not implicated modulation of regulatory and effector functions of cells of the monocyte/macrophage series as part of the immunologic effects of retinoids. To test directly for this possibility, we are establishing assays to assess the activity of RA on both activated and nonactivated macrophage/monocytes using phagocytosis and direct cytotoxicity as suitable parameters. RA will be included in the cultures either during the activation process (e.g., by supernatant from mitogen-stimulated PBL), during the assays for effector functions, or both. This appreach will allow us to distinguish the effects of RA on both the induction/antigen processing and effector phases of macrophage activity. Our in vitro studies have now demonstrated that RA can modulate both cellular and humoral immune responses in humans. In the next budget period, we will initiate a study of the immunomodulating activity of 13-cis RA (Accutane) in patients with severe Recalcitrant Cystic Acne in an ongoing clinical trial being conducted by the Department of Dermatology, UCLA School of Medicine. This study will involve immunizing patients with KLH (keyhele limpet hemacyanin) for studying Accutane modulation of primary and secondary responses to a protein antigen and tetanus toxoid for evaluating secondary responses to an antigen where the primary immunization had already occurred before Accutane administration. (HF)
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