Heterogeneity in fetal immunocompetence during the second trimester of gestation. Implications for treatment of nonimmune genetic disorders by in utero transplantation.

OBJECTIVE: To address the role that alloreactivity may play and better define the window for histoincompatible stem cell transplantation in utero. SUBJECTS, MATERIAL AND METHODS: We studied 9 fetal blood specimens obtained by cardiocentesis during elective abortions in the second trimester by multicolor flow cytometry and in vitro stimulation. RESULTS: Lymphocytes ranged from adult levels (3/9) to >90% leukocytes. Six specimens had T cells within adult range. T cells in the other specimens were reduced, while B cells were conversely elevated. This variability did not correlate with gestational age, or leukocyte composition. Following 4 h of mitogenesis, fetal CD4+ and CD8+ T cells from 1 of 5 specimens showed a response similar to that of maternal T cells, while the other 4 specimens showed a diminished response (0.3 +/- 0.2-fold). This heterogeneity did not correlate with gestational age, or lymphocyte subset distribution. Following 18 h of in vitro mitogenesis, fetal T cells from 2 specimens showed a response similar to that of maternal T cells (0.8 +/- 0.2-fold). Despite that, one specimen gave a 3-fold greater response in a one-way mixed lymphocyte reaction vs. maternal cells compared to the other specimen. CONCLUSION: We determine that fetal immunocompetence differs greatly during the second trimester and assessment of host vs. donor reactivity prior to in utero transplantation is likely to potentiate more favorable outcomes.

Mycobacterium tuberculosis-induced CXCR4 and chemokine expression leads to preferential X4 HIV-1 replication in human macrophages.

Opportunistic infections such as pulmonary tuberculosis (TB) increase local HIV-1 replication and mutation. As AIDS progresses, alteration of the HIV-1 gp120 V3 sequence is associated with a shift in viral coreceptor use from CCR5 (CD195) to CXCR4 (CD184). To better understand the effect of HIV/TB coinfection, we screened transcripts from bronchoalveolar lavage cells with high density cDNA arrays and found that CXCR4 mRNA is increased in patients with TB. Surprisingly, CXCR4 was predominately expressed on alveolar macrophages (AM). Mycobacterium tuberculosis infection of macrophages in vitro increased CXCR4 surface expression, whereas amelioration of disease reduced CXCR4 expression in vivo. Bronchoalveolar lavage fluid from TB patients had elevated levels of CCL4 (macrophage inflammatory protein-1beta), CCL5 (RANTES), and CX3CL1 (fractalkine), but not CXCL12 (stromal-derived factor-1alpha). We found that M. tuberculosis infection of macrophages in vitro increased viral entry and RT of CXCR4-using [corrected] HIV-1, but not of CCR5-using [corrected] HIV-1. Lastly, HIV-1 derived from the lung contains CD14, suggesting that they were produced in AM. Our results demonstrate that TB produces a permissive environment for replication of CXCR4-using virus by increasing CXCR4 expression in AM and for suppression of CCR5-using HIV-1 by increasing CC chemokine expression. These changes explain in part why TB accelerates the course of AIDS. CXCR4 inhibitors are a rational therapeutic approach in HIV/TB coinfection.