CONSTRAINTS ON CD4 RECOVERY POSTCHEMOTHERAPY IN ADULTS - THYMIC INSUFFICIENCY AND APOPTOTIC DECLINE OF EXPANDED PERIPHERAL CD4 CELLS

To examine the mechanisms of CD4 reconstitution in an adult population , lymphocyte repopulation was assessed following dose-intense chemothe rapy in 25 breast cancer patients, ages 33 to 69 years. Chemotherapy r esulted in a greater than 60% reduction in total CD4 T cells and, in p articular, a greater than 90% loss of the CD45RA(+) CD4 cells. CD4 rec overy was protracted, achieving less than 50% of pretreatment levels a fter 12 to 14 months, Two facets of the CD4 recovery were notable. Fir st, generation of CD45RA(+) CD4 cells played only a minor role in the first year, suggesting that thymic production was not the main route o f CD4 regeneration. Indeed, recovery of CD45RA(+) CD4 cell levels rema ined limited in half of the patients even after 2 years. Second, expan sion of the mature peripheral CD4 cells (CD45RO(+)) remaining after ch emotherapy was the main source of early CD4 repopulation, peaking at 3 to 6 months postchemotherapy. This expansion was limited in duration, however, and was followed by a secondary decline, such that the total CD45RO(+) CD4 levels at 9 to 12 months were lower than at 6 months. W hen stimulated by mitogens, an increased susceptibility to apoptosis w as observed in post-chemotherapy CD4 cells as compared with those from normal donors. The elevated expression of markers such as HLA-DR duri ng chemotherapy and for several months post-chemotherapy is consistent with the presence of an activated T-cell population. CD4 apoptotic fr equency correlated with the frequency of HLA-DR expression on T cells, Thus, CD4 recovery is constrained in adults by a limited thymic regen erative capacity and by an increased susceptibility to apoptosis withi n the expanding peripheral CD4 population.