Constraints on CD4 recovery postchemotherapy in adults: Thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells

Frances T. Hakim, Rosemarie Cepeda, Song Kaimei, Crystal L. Mackall, Nanette McAtee, Jo Anne Zujewski, Kenneth Cowan, Ronald E. Gress

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3789-3798
Number of pages10
JournalBlood
Volume90
Issue number9
StatePublished - Nov 15 1997

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Hakim, F. T., Cepeda, R., Kaimei, S., Mackall, C. L., McAtee, N., Zujewski, J. A., Cowan, K., & Gress, R. E. (1997). Constraints on CD4 recovery postchemotherapy in adults: Thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood, 90(9), 3789-3798.