Tolerance to A-Antigen After Treatment of Infant or Adult Mice with MHC-Matched A-Expressing Blood Cells

Student Researcher:
Jordana Fersovich

Supervisor / Principle Investigator:
Lori J West

Additional Authors:
Bruce Motyka
Brendon Lamarche
Kesheng Tao
Jean Pearcey
Christopher Cairo
Todd Lowary
Lori J West

MD Class of 2020

ABSTRACT

Introduction: ABO-incompatible heart transplantation (ABOi HTx) is safe in infants, increasing donor access. Post-ABOi HTx B cell tolerance develops to donor blood group antigen(s) by mechanisms not fully defined. We developed A-transgenic (A-Tg) mice that express A-antigen on endothelium and erythrocytes. Herein, we explored intentional tolerance induction in infant and adult WT mice using A-Tg blood cells (BC). Methods: WT BALB/c mice were injected ip (weeklyx3) with intact A-Tg BALB/c BC (±40Gy irradiated) at 7 days (neonates) or 5 months old (adults). After two weeks, all mice were injected ip (weeklyx5) with human A-RBC (A-sensitized) in an attempt to elicit anti-A antibody (Ab) production. Serum anti-A and 3rd-party (non-A anti-human) Ab were assessed by hemagglutination assay.

Results: Following A-sensitization, high levels of anti-A Ab were produced in untreated mice (median titre 1:256, n=11). In contrast, anti-A remained undetectable (≤1:2) in neonatal mice treated with irradiated (n=5) or non-irradiated A-Tg BC (n=6) (p < 0.0001). Adult mice treated with A-Tg BC produced less anti-A compared to untreated (p < 0.05). Adult mice without natural anti-A pre-treatment produced less anti-A (≤1:2 to 1:4, n=5) vs those with natural anti-A (1:16 to 1:64, n=5) (p < 0.05). Enriched A-Tg RBC-treated neonatal mice produced undetectable anti-A Ab (≤1:2, n=4), in contrast to those treated with enriched A-Tg PBMCs (≤1:2048, n=3) (p < 0.0001). Third-party Ab responses were high for all (≥1:128).

Conclusions: Our results suggest erythrocytes can induce robust A-antigen tolerance in WT mice. Further, A-antigen tolerance is not limited to neonates, but can also be induced in adults. Intentional tolerance induction may allow subsequent ABOi HTx.

 
 

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