Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease

Abstract

Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor b1 (TGF-b), a cytokine essential for the differentiation of tolerance-inducing CD4 + FoxP3 + regulatory T cells (Tregs). Consistent with this observation, treatment of na€ ıve murine T cells with PSG1 resulted in a significant increase in FoxP3 + cells that was blocked by a TGF-b receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-b in vivo. As the role of CD4 + FoxP3 + cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissueinfiltrating inflammatory CD3 + T cells and had increased expression of FoxP3 in T cells compared with vehicletreated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus-leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency. Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation.

Immunoregulatory potential of pregnancy-specific β1-glycoprotein

“…Medical Immunology (Russia)/Meditsinskaya Immunologiya Медицинская Иммунология PSG1 administration significantly reduced weight loss and mortality associated with a GVHD [18]. Interestingly, and consistent with our data, PSG9 induced Treg differentiation in vitro both at the level of human and mouse cells [17].…”

“…We assessed the role of PSG in the regulation of the production of basic cytokines and chemokines by immunocompetent human blood cells without additional inducers under conditions of 18 We found that when introduced into the culture of mononuclear cells, PSG reduced the production of proinflammatory cytokines IL-6, IL-8, IL-17, IFNγ, TNFα [40]. In general, the integral cytokine profile under PSG's action is formed as an anti-inflammatory (Th2).…”

Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy

“…The cell contact-independent mechanism of Tregs is achieved through the secretion of inhibitory cytokines, and TGF-β1 is essential for the proliferation and inhibitory activity of Tregs ( 53 ). The activation of TGF-β1 is necessary to induce the production of CD4 + FOXP3 + Tregs, and Tregs can then secrete TGF-β1 and participate in immune regulation ( 54 , 55 ). Studies have shown that TGF-β1 can promote the differentiation of initial CD4 + T cells into Tregs, and TGF-β1 secreted by Tregs can play a role in maintaining the inhibitory properties of Tregs by binding to its receptors.…”

Evolution of Placental Hormones: Implications for Animal Models

“…The case is stronger for a role in immune tolerance of the invading trophoblast, especially in humans where PSGs, acting through TGFβ1, induce proliferation of regulatory T-cells in the uterus ( 46 , 130 ). There is growing evidence for a similar mechanism in rodents ( 140 ) and there could be a link between PSG expression by the endometrial cups of the horse and the presence of regulatory T-cells in their vicinity ( 145 ).…”

“…Trophoblast giant cells express Psg22 in the first half of mouse pregnancy, whereas the spongiotrophoblast expresses Psg16 , Psg21 and Psg23 in the second half ( 138 ). Mouse Psg23 can activate latent TGFβ1 ( 139 ) and likely increases the availability of regulatory T-cells, as shown by administering recombinant human PSG1 to mice ( 140 ).…”