TOLERANCE TO HUMAN BLOOD GROUP A-ANTIGEN FOLLOWING EXPOSURE TO A-ANTIGEN IN INFANCY

LoriJ. West ⁰; Bruce Motyka ⁰; Yiqun Wang ⁰; Brendon Lamarche ⁰; Ibrahim Adam ⁰; Jean Pearcey ⁰; Kesheng Tao ⁰; ChristopherW. Cairo ⁰; PeterJ. Cowan ⁰

²Dept Pediatrics, Alberta Transplant Institute, Canadian National Transplant Research Program, Edmonton, AB, Canada; ³Dept Pediatrics, Alberta Transplant Institute, Edmonton, AB, Canada; ⁴Dept Chemistry, Alberta Glycomics Centre, Edmonton, AB, Canada; ⁵Immunology Research Centre, Melbourne, Canada

Introduction: In contrast to adults, ABO-incompatible heart transplantation (ABOi HTx) can safely be performed in infants due to absent/low levels of anti-A/B antibodies. Tolerance develops to donor blood group A/B-antigen after ABOi HTx by mechanisms not well-defined. Using a novel human blood group A-antigen transgenic (A-Tg; C57BL/6, B6) mouse model we showed A-antigen specific tolerance following HTx into young (4 weeks old) wild-type B6 (WT) mice. Herein, we explored tolerance induction to A-antigen in a form other than a transplant. A-Tg erythrocytes (RBC) express A-antigen at high levels. We hypothesized that treatment of infant WT mice (≤3 weeks old) with A-Tg RBC would induce A-antigen specific tolerance, allowing subsequent ABOi HTx.

Methods: WT mice were injected i.p. at age 7, 14, and 21 days with: 1) intact A-Tg RBC; 2) A-Tg RBC membranes; 3) human A RBC membranes (hA-RBCs); or 4) left untreated (Table). As adults (7 weeks), all mice were injected i.p. (weekly x4) with hA-RBC in an attempt to elicit anti-A antibody. Serum anti-A and third-party (non-A anti-human RBC) antibody were assessed by hemagglutination/ELISA.

Results: Following A-sensitization, high levels of anti-A antibody developed in untreated mice and mice neonatally-treated with hA-RBCs or A-Tg RBC membranes (Table). In contrast, anti-A antibody remained absent/low in A-sensitized mice treated as neonates with intact A-Tg RBC (Table); third-party antibody levels were high in all (median titre 1:64).

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Conclusion: The inability to elicit anti-A antibody in A-sensitized adult mice neonatally-treated with intact A-Tg RBCs, together with abundant production of third-party antibody, suggests development of robust A-Ag specific tolerance. Our findings suggest that the form of A-antigben (intact cells vs membrane), that may relate to antigen persistence, is critical to B cell tolerance in this setting. Intentional induction of tolerance to A/B-antigen(s) in infancy may allow later ABOi HTx.