Effects of Paternal Lymphocyte Immunization on Peripheral Th1/Th2 Balance and TCR Vbeta and VGamma Repertoire Usage of Patients with Recurrent Spontaneous Abortions

PROBLEM: The mechanism of immunotherapy for patients with recurrent spontaneous abortions is not well understood. In order to investigate the suppressor mechanism of paternal lymphocyte immunization, we examined peripheral blood lymphocyte subpopulations and the repertoire of T-cell receptor (TCR) gene segments. METHOD OF STUDY: Twelve patients with recurrent miscarriage were treated with immunization with paternal lymphocyte vaccinations three times during 12-14 weeks. Before and 2 weeks after the final inoculation, lymphocyte subsets and intra-cellular interferon (IFN)-gamma and/or interleukin (IL)-4 production were examined by flow cytometry. TCR V beta and V gamma repertoires were examined by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: We found no significant difference in CD4/CD8 ratios, prevalence of CD56(+) CD3(+) or CD57(+) CD3(+) cells (possible extrathymic T cells), gamma delta T cells, and CD5(+) CD19(+) (B-1) cells. However, by in vitro activation with phorbol 12-mytistate 13-acetate (PMA) and ionomycin, peripheral CD4 cells demonstrated a significant decrease of IFN-gamma-producing T helper 1 (Th1) cells and an increase of IL-4-producing T helper 2 (Th2) cells after immunotherapy. Seven of nine patients who exhibited remarkable decreases in Th1/Th2 ratios became pregnant within 6 months after three courses of immunotherapy, and four women delivered healthy babies, while none of the three patients who exhibited an increased or unchanged Th1/Th2 ratio had full-term pregnancies (chi(2) < 0.0001). Further, changes in usage of TCR V beta and V gamma gene segments were observed after immunotherapy in six patients examined. CONCLUSION: Our findings suggest a shift of Th1-dominant to Th1-dominant status by vaccination might play important roles in maintaining successful pregnancies. Induction of some T cells that utilize different TCR repertoires possibly suppresses maternal rejection reactions.