transforming-growth-factor-beta and Leukopenia

Human CD34+ hematopoietic progenitor cells, stringently purified from the peripheral blood of 20 normal donors, showed an impaired survival and clonogenic capacity after exposure to either heat-inactivated human immunodeficiency virus (HIV) 1 (strain IIIB) or cross-linked envelope gp120. Cell cycle analysis, performed at different times in serum-free liquid culture, showed an accumulation in G0/G1 in HIV-1- or gp120-treated cells and a progressive increase of cells with subdiploid DNA content, characteristic of apoptosis. In blocking experiments with anti-transforming growth factor (TGF) beta 1 neutralizing serum or TGF-beta 1 oligonucleotides, we demonstrated that the HIV-1- or gp120-mediated suppression of CD34+ cell growth was almost entirely due to an upregulation of endogenous TGF-beta 1 produced by purified hematopoietic progenitors. Moreover, by using a sensitive assay on the CCL64 cell line, increased levels of bioactive TGF-beta 1 were recovered in the culture supernatant of HIV-1/gp120-treated CD34+ cells. Anti-TGF-beta 1 neutralizing serum or TGF-beta 1 oligonucleotides were also effective in inducing a significant increase of the plating efficiency of CD34+ cells, purified from the peripheral blood of three HIV-1-seropositive individuals, suggesting that a similar mechanism may be also operative in vivo. The relevance of these findings to a better understanding of the pathogenesis of HIV-1-related cytopenias is discussed.

Topics: Antigens, CD34; Base Sequence; Cell Cycle; Cells, Cultured; Culture Media, Serum-Free; Female; Hematopoietic Stem Cells; HIV Envelope Protein gp120; HIV Seropositivity; HIV-1; Humans; Leukopenia; Male; Molecular Sequence Data; Oligonucleotides, Antisense; Recombinant Proteins; RNA, Messenger; Transforming Growth Factor beta; Up-Regulation

We have developed a mouse model to utilize the specific regulatory effects of Transforming Growth Factor Beta-1 (TGF beta 1), the prototype for a family of growth inhibitory cytokines. A vital factor in the regulation of normal cellular growth for many cell types, TGF beta 1 prevents proliferation by reversibly arresting cells at the G1/S border of the cell cycle, thus delaying DNA synthesis and cell division. Since the dose of cytotoxic chemotherapy is limited by its adverse effects on bone marrow and gut cells, we proposed that a TGF beta 1-induced block at G1/S would diminish the S phase toxicity of high dose cytarabine (ara-C). The dosage of ara-C required to kill 90 per cent of 4-week old DBA/2 males was determined to be 3200 mg/kg every 12 hours x 2. Pretreatment with TGF beta 1 6-24 hours before the first dose of ara-C proved to be significantly protective; 8/9 TGF beta 1-pretreated mice survived versus 1/9 treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 10.89 P = 0.001). A second experiment confirmed this effect; TGF beta 1 pretreatment for 6-24 hours protected 9/9 versus 0/9 survivors in the group treated with TGF beta 1 for 3 hours or less or with ara-C alone (chi2 = 18.0, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cytarabine; Digestive System; Drug Administration Schedule; Erythrocyte Count; Hematopoietic Stem Cells; Leukocyte Count; Leukopenia; Male; Mice; Mice, Inbred A; Mice, Inbred DBA; Mice, Inbred Strains; Neutropenia; Platelet Count; S Phase; Stem Cells; Survival Rate; Transforming Growth Factor beta