Enhancing effects of locally administered cytostatic drugs on T effector cell functions in mice

It is well established that systemic treatment with cyclophosphamide (CY) can augment cell-mediated immunity by selective toxicity for suppressor cells. The present paper analyzes the effect of local administration of the cytostatic drugs Z 7557, an active CY-derivative, and VP-16 (etoposid) on the development of cell-mediated immunity to KLH in mice. Both drugs were found to induce a long-lasting state of enhanced DTH responsiveness. Induction of enhancement was antigen-specific but required a conjunction of local drug treatment and s.c. priming. This indicates that locally applied cytostatics interact with the sensitizing process in the draining lymph node. In support of this view, draining lymph node cells showed an enhanced capacity to transfer DTH reactivity to syngeneic recipients in vivo, and to proliferate and produce IL-2 and MIF in response to KLH in vitro. Kinetic studies showed a lag in appearance of antigen-specific T cell responsiveness in drug treated mice, which indicates that effector cells are also sensitive to the drugs. If local chemotherapy is properly scheduled, the effector cells recover quickly and, released from the putative inhibitory influence of suppressor cells, give rise to an augmented T cell response. As systemic treatment with cytostatic drugs is known to cause adverse side effects, restricting its use for immunopotentiating purposes, the present local chemotherapy protocol provides a new, versatile approach for enhancing cell-mediated immunity.