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, 104 (1), 80-6

Medroxyprogesterone Acetate Enhances in Vivo and in Vitro Antibody Production

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Medroxyprogesterone Acetate Enhances in Vivo and in Vitro Antibody Production

M Vermeulen et al. Immunology.

Abstract

In the present study we examine the effects of medroxyprogesterone acetate (MPA) on the specific antibody secretion to T-dependent antigens. Our results show that the in vivo administration of MPA to mice, 7 or 90 days before immunization with sheep red blood cells (SRBC), significantly enhanced both, primary and secondary antibody responses, without affecting delayed-type hypersensitivity (DTH). These effects could be counteracted by the anti-progestin onapristone or ZK 98299 (ZK) suggesting that MPA interacted with progesterone (PRG) receptors to increase B-cell response. To better understand the mechanisms involved in MPA activity we carried out cultures of splenocytes, bone marrow cells or lymph node cells from immunized mice in the presence of MPA, and evaluated the amount of antibody release to supernatants. We found that low doses of MPA (10(-9) M and 10(-10) M) significantly enhanced the in vitro production of specific immunoglobulin G (IgG) antibodies, an effect that appears to involve the interaction of the progestin with PRG receptors, as judged by the inhibition of MPA effects with ZK (10(-8) M) or RU486 (10(-9) M). These receptors were detected by flow cytometry analysis in a proportion of T lymphocytes. Because MPA did not increase the number of immunoglobulin-secreting cells, our findings suggest that MPA enhanced the capacity of individual cells to produce specific immunoglobulin.

Figures

Figure 1
Figure 1
ZK98299 inhibits MPA-induced enhancement of antibody response. Mice were injected s.c. with 10 mg/kg/daily of ZK from the day of MPA depot (40 mg s.c.) inoculation until the day of immunization with SRBC. Primary antibody response (a) was evaluated as described in Materials and Methods. To determine whether the antiprogestin can counteract the enhancing effect of MPA on secondary response (b), ZK was administered as a 1·7-mg silastic pellet implanted s.c. Data represent the mean ± SEM of six animals. *P < 0·05 MPA versus control; **P < 0·05 MPA ± ZK versus MPA.
Figure 2
Figure 2
MPA increases the release of specific antibodies in vitro. Mice were immunized with SRBC or OVA as described in Materials and Methods for primary response. Splenocytes from mice immunized with SRBC (a and c) and lymph node cells from mice immunized with OVA (b and d) were cultured in vitro with different concentrations of MPA (a and b) or MPA 10−10 m, LPS 10 µg/ml or saline (c and d) during 7 days. The production of anti-SRBC IgG was determined by flow cytometry and expressed as mean fluorescence intensity (MFI). The production of anti-OVA Immunoglobulin was determined by ELISA in samples diluted 1 : 40 and expressed as absorbance values at 492 nm. Hatched bars represent antibody released from non-immunized cells and black bars from immunized cells. Results are expressed as the mean ± SEM of seven to10 animals. *P < 0·05 MPA or LPS versus saline.
Figure 3
Figure 3
MPA in vitro increases IgM and IgG1 release from OVA-immunized lymph node cells. Cells from OVA-draining lymph nodes were cultured in vitro with MPA 10−10 m (black bar) or saline (open bar). Seven days later, the release of IgM, IgG1, IgG2a and IgE was determined by ELISA in samples diluted 1 : 40 and expressed as absorbance values at 492 nm. Data represent the mean ± SEM of seven animals. *P < 0·01 MPA versus saline.
Figure 4
Figure 4
A subset of T lymphocytes in lymph nodes express PRG receptors. Expression of PRG receptors in lymph node cells was analysed by flow cytometry as described in Materials and Methods. (a) Solid histogram indicates control labelling with an irrelevant mAb, open histogram shows staining with specific mAb. (b) Two-colour fluorescence analysis for PRG receptors and CD3. Lymph node cells were labelled with an irrelevant mAb (left dot plot) or anti-PRG receptor mAb (right dot plot) before staining with anti-CD3-PE. Results are representative of four experiments performed.
Figure 5
Figure 5
MPA does not increase the number of anti-OVA secreting lymph node cells. Cells from distal lymph nodes (hatched bars) or OVA-draining lymph nodes (black bars) were cultured in vitro with MPA (10−10 m), LPS (10 µg/ml) or saline. Five days later, the number of anti-OVA secreting cells was measured by ELISPOT. Data are expressed as the mean ± SEM of five animals. *P < 0·01 LPS versus saline.

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