Donor major histocompatibility complex class I expression determines the outcome of prenatal transplantation

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Abstract

Purpose

The failure of in utero transplantation in immune-competent recipients suggests the existence of a fetal immune barrier. The importance of donor major histocompatibility complex (MHC) class I expression in the induction of prenatal tolerance remains undefined. We hypothesized that donor cell MHC class I expression facilitates engraftment in prenatal allogeneic recipients rather than promoting immune rejection.

Methods

B6.Ly5.2 (class I+) or B6.TAP−/− (class I) murine fetal liver cells were transplanted into age-matched allogeneic fetal recipients. Survival to weaning and subsequent growth was assessed. Engraftment rates and peripheral blood chimerism levels were measured serially.

Results

The presence or absence of class I expression did not affect survival or growth of recipients and no graft-vs-host disease developed. Allogeneic recipients of B6.Ly5.2 cells exhibited significantly higher levels of donor hematopoietic chimerism when compared to recipients of B6.TAP−/− cells (27% + 10% vs 11% + 8%; P = .004) that deteriorated further over time.

Conclusions

Donor class I MHC antigen expression is essential for stable long-term engraftment and maintenance of donor-specific tolerance. Further studies are needed to better characterize the role of the fetal innate immune system in prenatal allotransplantation.

Section snippets

Mice

Breeding stock for inbred strains of mice B6.Ly5.2 (H2b, Ly5.2+), SJL/J (H2s, Ly5.1+) (The Jackson Laboratories, Bar Harbor, Me), Balb/c (H2d, Ly5.2+) (Charles River Laboratories, Wilmington, Mass), and B6.TAP−/− (H2b, Ly5.2+) (Taconic, Germantown, NY) were purchased and bred in our colony. CSJLF1 (Balb/c × SJL/J F1, H2s/d, Ly5.1+Ly5.2+) mice were bred in our colony. Animals were mated and inspected daily for introital plugging. Day of plug was noted as day zero for time-dated pregnancies. All

The presence or absence of MHC class I expression by the donor cells does not affect survival or lead to graft-vs-host-disease

Four murine strains were selected to evaluate the allogeneic host response to MHC class I expression after IUCT (Fig. 1). The B6.Ly5.2 strain carries the H2b haplotype and is fully allogeneic with Balb/c recipients that bear the H2d haplotype. The B6.TAP−/− donor strain was chosen for the experimental group because it is deficient in the transporter associated with antigen presentation (TAP) and therefore does not express any MHC class I antigen but are otherwise identical with the parent

Discussion

The bias of IUCT that has existed for many years is that transplantation before the development of the adaptive immune system results in long-term donor-specific tolerance. However, the limited success of IUCT in clinical cases that do not involve immunodeficiency diseases forces a closer examination of this central dogma [9]. Recently, it has been postulated that an allogeneic barrier to the development of fetal tolerance may exist because of differences in donor cell MHC expression [4]. The

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      Moreover, cell surface antigen expression can be manipulated either genetically or pharmacologically. For example, some studies have eliminated MHC-I expression in donor cells, although this did not appear to increase engraftment but, rather, led to rejection of the implanted cells (Durkin et al. 2008). However, a possible reason for this observation is the loss of the immunosuppressive MHC-Ib subtype along with the immunogenic MHC-Ia subtype (Rodgers and Cook 2005).

    Presented at the 59th Annual Meeting of the Section on Surgery, American Academy of Pediatrics, San Francisco, CA, October 25-27, 2007.

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