*Purpose: ABO-mediated immunity is reported to have minimal detrimental impact after ABO-mismatched hematopoietic cell transplantation (HCT). Patients are generally presumed ‘tolerant’ with regard to ABO. However, this has not been systematically evaluated, nor have ‘solid-phase’ assays been used for detection of ABO antibodies (Ab). A unique aspect post-HCT is immune reconstitution including delayed responses to polysaccharides, similar to normal infant development. We hypothesized that dynamics of immune reconstitution post-HCT mimics infant development, leading to ABO tolerance, and that ABO antibody solid-phase technology will yield accurate information allowing investigation of tolerance.

*Methods: Through the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study (Cuvelier et al. 2019, Blood) plasma samples were collected from 287 patients at 27 sites at timepoints pre-HCT/pre-conditioning and 3, 6, 12 and 24 months post-HCT. Age at HCT was 0.2-17.9 (median 9.3) years. Donors and recipients were ABO-typed. Of HCT, 47% were ABO-mismatched. ABO Ab, including isotype and ABH-subtype specificity, was assessed by our newly-developed ABH-glycan microarray (Jeyakanthan et al. 2016, Amer J Transplant).

*Results: Ab to recipient A/B antigens were undetectable in most patients after ABO-mismatched HCT (O into A; O into B; O into AB). In contrast, Ab to ‘third-party’ A/B antigens and alpha-gal (a-gal) were detected in most patients pre- and post-ABO-matched/mismatched HCT. ‘O into A’ patients are shown in Fig 1A: most have undetectable IgM and IgG anti-A (subtypes I-IV) Ab both pre- and post-HCT, whereas anti-B and anti-a-gal Ab were detected (although not in all patients) pre- and post-HCT. In comparison, IgM and IgG anti-A and anti-B subtype I-IV Ab (and a-gal) were present at variable levels in ABO-matched ‘O into O’ patients (Fig 1B).

*Conclusions: The absence of Ab to recipient A/B antigens in the presence of third-party ABO/a-gal Ab after ABO-mismatched HCT is consistent with development of recipient-specific ABO tolerance in the donor-derived immune system. Delineating mechanisms of ABO tolerance in the HCT environment using solid-phase technologies may lead to more opportunities for safe ABOi solid organ transplantation.

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