Daljeet Banwatt

Stress-triggered abortion in mice prevented by alloimmunization

PROBLEM: To determine if immunotherapy can prevent abortion triggered by mechanisms that in humans may be treatable by psychotherapy.

A subset of patients with recurrent spontaneous abortion is deficient in transforming growth factor β-2-producing suppressor cells in uterine tissue near the placental attachment site

PROBLEM: To determine if patients with unexplained recurrent miscarriage have a deficiency of decidual immunosuppressor cells that produce transforming growth factor β type 2, as has been found in mice with abortion due to rejection and/or trophoblast failure.

Decidua-associated suppressor activity and viability of individual implantation sites of allopregnant C3H mice.

Release of soluble suppressor activity from individual implant site decidua of DBA/2-mated C3H/HeJ mice was measured on days 12.5-13.5 of pregnancy. Suppressor activity varied among sites and followed a distribution curve that was displaced towards low suppression when resorption sites were compared to healthy embryonic implants. Pre-immunization against the DBA/2 strain paternal antigens failed to increase resorption (by loss of low suppression implants) but led instead to a reduced resorption rate. This was associated with an increase in soluble suppressor activity obtained from decidua. Some reduction in resorption occurred independent of an increase in the level of suppression suggesting additional contributing factors to the immunization effect.

Prevention of spontaneous abortion in the CBA x DBA/2 mouse model by intravaginal TGF-beta and local recruitment of CD4+8+ FOXP3+ cells.

Activation of latent transforming growth factor (TGF)‐β in seminal plasma has been suggested by Robertson et al. to promote maternal tolerance to paternal antigens. A possible consequence reported by Tremellen et al. is increased pregnancy rates in women undergoing IVF. A decreased spontaneous abortion rate has also been postulated. Seminal plasma contains many factors besides TGF‐β, and a critical test of the hypothesis was required. The purpose of the present study was to directly test the effect of pure TGF‐β.

ORIGINAL ARTICLE: Prevention of Spontaneous Abortion in the CBA × DBA/2 Mouse Model by Intravaginal TGF-β and Local Recruitment of CD4+ 8+ FOXP3+ Cells

Activation of latent transforming growth factor (TGF)‐β in seminal plasma has been suggested by Robertson et al. to promote maternal tolerance to paternal antigens. A possible consequence reported by Tremellen et al. is increased pregnancy rates in women undergoing IVF. A decreased spontaneous abortion rate has also been postulated. Seminal plasma contains many factors besides TGF‐β, and a critical test of the hypothesis was required. The purpose of the present study was to directly test the effect of pure TGF‐β.

Hormone-induced preimplantation Lyt 2+ murine uterine suppressor cells persist after implantation and may reduce the spontaneous abortion rate in CBA/J mice

Immunoregulatory cells in the maternal uterine endometrium and decidua are thought to play an important role in ensuring the success of the semiallogeneic conceptus. Two phases of suppression have been described in pregnant mice. Prior to implantation, the hormonal changes triggered by mating activate or recruit a population of nonspecific Lyt 2+ suppressor cells that inhibit cytotoxic T lymphocyte generation: this suppression appears to wane at the time or implantation and 4-5 days after implantation, a non-T suppressor cell population activated or recruited by fetal trophoblast cells develops. In this paper we confirm the non-major histocompatibility complex specificity of the hormone-regulated preimplantation suppressor cell. We show that this activity persists in the uterus during the early postimplantation period where its suppressive activity is masked by an Fc-receptor-positive cell population recruited by the implanting embryo. The potential importance of the persisting suppressor cells is suggested by an increase in the rate of spontaneous abortion of DBA2-mated CBA/J mice following injection of monoclonal anti-Lyt 2+ antibody in the early postimplantation period.

Spontaneous Abortion in Immunodeficient SCID Mice

PROBLEM: Immunodeficient SCID mice on the CB‐17 have been used to test the role of “rejection” in a xenogeneic blastocyst transfer model of recurrent miscarriage, but interpretation of the data requires knowing syngeneic within‐species matings have a high success rate and do not require immunotrophic factors expected only in immunocompetent non‐T‐cell deficient mice.

Murine Trophoblast Failure and Spontaneous Abortion

PROBLEM: Infection has been proposed to initiate abortion, and the role of viruses in spontaneous resorption in mice has not been tested.

ORIGINAL ARTICLE: Ecology of Danger-Dependent Cytokine-Boosted Spontaneous Abortion in the CBA × DBA/2 Mouse Model: II Fecal LPS Levels in Colonies with Different Basal Abortion Rates

Problem  Previous data have shown that ‘danger’ signals, such as bacterial lipopolysaccharide (LPS) acting via toll‐like receptors (TLR), are conditions antecedent to early pregnancy failure in several murine abortion models. Indeed, the abortion rate increased in the CBA × DBA/2 model after injection of tumor necrosis factor‐α (TNF‐α) + interferon (IFN‐γ) on gestation day (GD) 7.5 only if the LPS–TLR signaling pathway was intact. High rates of cytokine‐boosted abortion >80% loss can be demonstrable in certain animal colonies that have a high endogenous (spontaneous) rate of resorption (30–50%). A specific role for LPS on GD 0.5 determines the endogenous loss rate and on GD 6.5 the responsiveness to cytokine boosting of losses. Th1 cytokines (or the stress that induces these cytokines) increase intestinal permeability and absorption of luminal contents. It was predicted that intestinal availability of LPS was a major factor in the endogenous and cytokine‐boosted resorption rates.

Ecology of danger-dependent cytokine-boosted spontaneous abortion in the CBA x DBA/2 mouse model: II. Fecal LPS levels in colonies with different basal abortion rates.

Problem  Previous data have shown that ‘danger’ signals, such as bacterial lipopolysaccharide (LPS) acting via toll‐like receptors (TLR), are conditions antecedent to early pregnancy failure in several murine abortion models. Indeed, the abortion rate increased in the CBA × DBA/2 model after injection of tumor necrosis factor‐α (TNF‐α) + interferon (IFN‐γ) on gestation day (GD) 7.5 only if the LPS–TLR signaling pathway was intact. High rates of cytokine‐boosted abortion >80% loss can be demonstrable in certain animal colonies that have a high endogenous (spontaneous) rate of resorption (30–50%). A specific role for LPS on GD 0.5 determines the endogenous loss rate and on GD 6.5 the responsiveness to cytokine boosting of losses. Th1 cytokines (or the stress that induces these cytokines) increase intestinal permeability and absorption of luminal contents. It was predicted that intestinal availability of LPS was a major factor in the endogenous and cytokine‐boosted resorption rates.