The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Camden, New Jersey, 7447 Old York Road, Melrose Park, PA 19027, USA
Correspondence: E-mail: laurie{at}ccivf.com
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I read with interest the manuscript by Makhseed et al. (Makhseed et al., 2001). They suggest recurrent aborters who subsequently have a normal delivery still have a greater Th1 cytokine bias than normal pregnant women, but have less of a Th1 bias than recurrent aborters who subsequently abort. They believe that their data `may pave the way for the development of methods to manipulate the maternal immune system towards a Th2-type situation that would favour the success of pregnancy'.
I believe that I know of a treatment modality that would restore the proper immunological milieu. However, it is not a new, complicated immune therapy, but a rather an old, well-recognized treatment of using extra progesterone supplementation (Check et al., 1987, 1988
).
Data have been presented that a shift of Th1 to Th2 cytokines and suppression of natural killer cell cytolytic activity may be under the control of an immunomodulatory protein known as progesterone-induced blocking factor (PIBF) (Szekeres-Bartho et al., 1996, 1989a
). PIBF is secreted by
/
T cells (Polgar et al., 1999
). The production of PIBF requires the de-novo synthesis of progesterone receptors by an allogenic stimulus in these
/
T cells (Szekeres-Bartho et al., 1985
, 1990
; Chiu et al., 1996
). The interaction of progesterone with progesterone receptors in
/
T cells leads to PIBF secretion (Szekeres-Bartho et al., 1999
). The exact nature of the paternal antigen that stimulates the progesterone receptor on
/
T cells is not known, but it may be a class 1 or class 1-like molecule (Van Kaer et al., 1991
).
Thus insufficient PIBF secretion, which would lead to Th1 dominance over Th2, could theoretically occur if there is insufficient progesterone production during pregnancy, or if there is maternal/paternal sharing of certain class 1 antigens so that there is a weakened paternal antigen. There are data showing low levels of PIBF in pregnant women who abort compared with controls with normal pregnancies (Szekeres-Bartho et al., 1989b, 1995
). However, another study demonstrated that in women who are aggressively treated with progesterone during the first trimester, there are no differences in PIBF expression by lymphocytes in aborters versus non-aborters (Check et al., 1997b
).
I suspect that when the authors mentioned paving the way to develop methods to manipulate the immune system they may have been referring to treatment modalities, e.g. lymphocyte immunotherapy, i.v. globulin, corticosteroids, or drugs such as etanercept or infliximab that suppress tumour necrosis factor
. Indeed, we have presented data suggesting that lymphocyte immunotherapy can improve fecundity in progesterone-supplemented women who have recurrent spontaneous abortions (Check et al., 1995
). Furthermore, we have demonstrated that lymphocyte immunotherapy can increase PIBF expression (Check et al., 1997a
). My suggestion, though, is that this group who seem to respond to immune manipulation would be only a minority of women who have inadequate induction of progesterone receptors and thus a Th1 bias in
/
T cells. The majority will merely respond to aggressive supplementation of progesterone.
I suggest that in future studies of their cytokine model in aborters versus the normal population, the authors evaluate whether they still find a Th1 bias in progesterone treated aborters and to evaluate the Th1/Th2 ratio in women with abortuses that proved to have normal karyotypes versus women with successful deliveries. Possibly it will be this small subgroup that may be the best one to evaluate `methods to manipulate the immune system'.
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References |
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