Effects of a multidrug chemotherapy regimen on the thymus.

Abstract

Multidrug chemotherapy regimens are commonly used in the treatment of cancer. The dose limiting tissue for chemotherapeutic treatment is often the bone marrow, as many chemotherapeutic agents selectively target rapidly proliferating cells. Bone marrow transplantation (BMT) has allowed an increase in chemotherapeutic dose; however, this type of therapy is associated with a prolonged suppression of immune function following the BMT. Although it may be possible to augment this immune function, animal models which can be used to test various cytokines have not been well described. We have developed a mouse model of multi-drug chemotherapy which, like the human, demonstrates long term immune suppression following BMT. In this report, we describe the specific effects of this chemotherapy regimen on T cell differentiation in the thymus of treated mice using three color FACS analysis. Results demonstrated that specific populations of thymocytes are extremely susceptible to chemotherapeutic insult. Both thymus cellularity and the immature CD3-CD4+CD8+ double positive population dropped to approximately 3% of their original values by 7 days after chemotherapy initiation. During the same time period, cells expressing both alpha beta and gamma delta T cell receptors demonstrated a 2-6 fold increase in frequency. Similar results were observed for the alpha beta+ CD4-CD8- population of natural suppressor cells. Long-term changes in the proportion of cells expressing the V beta 5 TCR were also observed following chemotherapy. These results demonstrate that chemotherapy regimens may directly influence T cell differentiation within the thymus, and also suggest that long term changes in the T cell V beta repertoire may occur following chemotherapy.