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Front. Immunol. | doi: 10.3389/fimmu.2018.00418

In Utero Exposure to Exosomal and B-cell Alloantigens Lessens Alloreactivity of Recipients’ Lymphocytes Rather Than Confers Allograft Tolerance

 Jeng-Chang Chen1*, Liang-Shiou Ou2,  Cheng-Chi Chan3,  Ming-Ling Kuo3, Li-Yun Tseng4 and Hsueh-Ling Chang4
  • 1Department of Surgery, Chang Gung Children's Hospital, Taiwan
  • 2Division of Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Children's Hospital, Taiwan
  • 3Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taiwan
  • 4Pediatric Research Center, Chang Gung Children's Hospital, Taiwan

According to actively acquired tolerance, antigen exposure before full immune development in fetal or early neonatal life will cause tolerance to this specific antigen. In this study, we aimed to examine whether allogeneic tolerance could be elicited by in utero exposure to surface MHC antigens of allogenic cells or soluble form of MHC exosomes. Gestational day 14 FVB/N fetuses were subjected to intraperitoneal injection of allogeneic major histocompatibility complex (MHC) exosomes or highly enriched B-cells. Postnatally, the recipients were examined for the immune responses to donor alloantigens by lymphocyte proliferative reactions and skin transplantation. In utero exposure to allogeneic MHC exosomes abolished the alloreactivity of recipients’ lymphocytes to the alloantigens, but could not confer skin allograft tolerance. In utero transplantation of highly enriched allogeneic B-cells generated low-level B-cell chimerism in the recipients. However, it only extended the survivals of skin allograft by a few days despite the lack of donor-specific alloreactivity of recipients’ lymphocyte. Thus, an early in utero contact with exosomal or B-cell alloantigens did not lead to full skin tolerance but rather, at best, only to delayed skin rejection in the presence of microchimerism made by B-cell inocula. These results argued against the theory of actively acquired tolerance, and implicated that in utero exposure to marrow cells in previous studies was a unique model of allo-tolerance induction that involved the establishment of significant hematopoietic chimerism. Taken together with the discovery of in utero sensitization to ovalbumin in our previous studies, the immunological consequences of fetal exposure to foreign antigens might vary according to the type or nature of antigens introduced.

Keywords: alloreactivity, B-cells, exosome, in utero injection, Major Histocompatibility Complex, Tolerance induction

Received: 27 Sep 2017; Accepted: 15 Feb 2018.

Edited by:

Joanna Davies, San Diego Biomedical Research Institute, United States

Reviewed by:

Alain Le Moine, Université libre de Bruxelles, Belgium
Ana C. Zenclussen, Medizinische Fakultät, Universitätsklinikum Magdeburg, Germany  

Copyright: © 2018 Chen, Ou, Chan, Kuo, Tseng and Chang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Jeng-Chang Chen, Chang Gung Children's Hospital, Department of Surgery, Taoyuan, Taiwan,