Fetal Tolerance to Maternal Antigens Improves the Outcome of Allogeneic Bone Marrow Transplantation by a CD4+CD25+ T Cell-Dependent Mechanism.
Authors: Matsuoka Ken-ichi , Ichinohe Tatsuo , Asakura Shoji , Hashimoto Daigo , Tanimoto Mitsune , Teshima Takanori 
Published: October 2019

Abstract
The lack of donor availability is a major limitation to the widespread use of allogeneic HSCT and therefore it would be beneficial to identify permissible HLA mismatches. The maternal and fetal antigens which are transmitted through the bi-directional transplacental passage during pregnancy may induce tolerance to noninherited maternal antigens (NIMAs) in offspring and to inherited paternal antigens (IPAs) in the mother. Using mouse models of BMT, we investigated whether fetal-maternal tolerance could affect the outcome of allogeneic BMT. To generate NIMA-exposed mice, we used the F1 x P backcross breeding schema. A B6 (H-2b) male and a B6D2F1 (H-2b/d) female were mated to generate H-2b/b offspring that was exposed to NIMA-H-2d in utero. To generate IPA-exposed mice, a female B6 mouse was mated with a male B6D2F1 mouse and was exposed to IPA-H-2d from her H-2b/d offspring. First, to examine the influence of the NIMA/IPA exposure on the alloreactive T cell responses to the corresponding antigens in vitro, CD4+ T cells isolated from these mice were cultured with B6D2F1 stimulators. Proliferation and IFN-gamma production of T cells from NIMA-exposed mice in response to NIMAs were significantly reduced in comparison to those from the controls, but T cells from IPA-exposed mice did not reduce reactivity to IPAs. We then performed allogeneic BMT from NIMA-exposed donors. Lethally irradiated B6D2F1 mice were transplanted with 5x106 TCD BM from the control B6 mice together with 2x106 T cells from either 8 week-old NIMA-exposed or control B6 donors. GVHD mortality was significantly less in recipients of a NIMA-exposed donor than in those of a control donor (28% vs 84% on day 80, p<0.005). When transplanted to third-party B6C3F1 (H-2b/k) recipients, no protective NIMA effect was observed, thus demonstrating the antigen-specificity of the NIMA-effects. In contrast, BMT from an IPA-exposed donor did not reduce GVHD in comparison to BMT from a control donor. We then studied the effects of NIMA complementary transplantation on both subsequent T cell reconstitution and graft-versus-leukemia (GVL) effect. T cell reconstitution was significantly improved in NIMA-recipients in comparison to that in the allogeneic controls 40 days after BMT (p<0.05). The number of double positive thymocytes was also significantly higher in the recipients of NIMA-exposed donors than in those of the controls (p<0.05). In GVL experiments, 2.5x104 host-type P815 leukemia cells (H-2d), that were uniformly lethal to the recipients of syngeneic BMT by day 20 after BMT, were injected to recipients of allogeneic BMT on day 0. Allogeneic BMT from a control donor and a NIMA-exposed donor significantly delayed the leukemia relapse (p<0.005), thus demonstrating that NIMA complementary transplantation did not abrogate GVL effect. Lastly, we examined whether CD4+CD25+ T cells mediate the NIMA effect. The tolerogenic NIMA effect was completely abolished by the depletion of CD4+CD25+ cells from the donor inoculums, thus suggesting the involvement of CD4+CD25+ regulatory T cells in the tolerogenic NIMA effects. Our findings have profound implications on clinical HSCT, they suggest that the use of a NIMA-mismatched donor in the absence of a HLA-identical donor may be a potentially effective treatment strategy.