Abstract
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.
Highlights
According to Medawar’s actively acquired tolerance [1], the immune system before full maturation undergoes a critical education so as to learn the discrimination between self and non-self
Exosome extracts were quantified by Bicinchoninic Acid (BCA) protein assays with its protein concentration linearly associated with A20 cell number used for exosome generation (Figure 1A)
We examined whether FVB/N (H-2q) lymphocytes had allogeneic proliferative responses to major histocompatibility complex (MHC) exosomes
Summary
According to Medawar’s actively acquired tolerance [1], the immune system before full maturation undergoes a critical education so as to learn the discrimination between self and non-self. In Utero Alloantigen Exposure favorable period for the implementation of medical interventions that will be later hampered by immune responses Such an idea has attracted widespread attention of transplantation community to prenatal allo-tolerance induction across major histocompatibility complex (MHC) barriers. Soluble forms of MHC have been described in mouse and human sera [12, 13] as cell-derived secretory vesicles of exosomes [14, 15], derived from antigen-presenting cells (APCs), such as dendritic cells [16,17,18,19], B-cells [20], and mast cells [21, 22] Their transfer to hosts through transfusion has been suggested to result in immunomodulatory effects [23]. It prompted us to examine whether B-cell inocula or soluble form of MHC exosomes were effective in prenatal induction of donor-specific tolerance
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