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 chemotherapy in 25 breast cancer patients, ages 33 to 69 years. Chemotherapy resulted in a greater than 60% reduction in total CD4 T cells and, in particular, a greater than 90% loss of the CD45RA+ CD4 cells. CD4 recovery was protracted, achieving less than 50% of pretreatment levels after 12 to 14 months. Two facets of the CD4 recovery were notable. First, generation of CD45RA+ CD4 cells played only a minor role in the first year, suggesting that thymic production was not the main route of CD4 regeneration. Indeed, recovery of CD45RA+ CD4 cell levels remained limited in half of the patients even after 2 years. Second, expansion of the mature peripheral CD4 cells (CD45RO+) remaining after chemotherapy 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. When stimulated by mitogens, an increased susceptibility to apoptosis was observed in postchemotherapy CD4 cells as compared with those from normal donors. The elevated expression of markers such as HLA-DR during chemotherapy and for several months postchemotherapy is consistent with the presence of an activated T-cell population. CD4 apoptotic frequency correlated with the frequency of HLA-DR expression on T cells. Thus, CD4 recovery is constrained in adults by a limited thymic regenerative capacity and by an increased susceptibility to apoptosis within the expanding peripheral CD4 population.
Hakim
F T
FT
Medicine Branch and Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Cepeda
R
R
Kaimei
S
S
Mackall
C L
CL
McAtee
N
N
Zujewski
J
J
Cowan
K
K
Gress
R E
RE
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D008875:Middle Aged; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology
D015704:CD4 Antigens