Failure of Neonatal B-Cell Tolerance Induction by ABO-Incompatible Kidney Grafts in Piglets

Jeyakanthan, M.; Zhou, Xianpei; Tao, K.; Mengel, Michael; Rajotte, Ray V.; Larsen, I.; West, Lori J.

doi:10.1097/tp.0b013e31829b0840

Cited by 4 publications

(1 citation statement)

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“…Blood cell membranes (BCMs) were prepared from pooled human reagent ABO-A 1 erythrocytes (Immucor Inc, Dartmouth, NS, Canada) described in detail elsewhere. 37 (Note that although not recorded in commercial product information, pooled reagent human erythrocytes are assumed to include cells from donors of both sexes.) Briefly, cells were washed in PBS and lysed in hypotonic buffer, and membranes were isolated after multiple centrifugations at 20 000 g .…”

Section: Methodsmentioning

confidence: 99%

Sex, T Cells, and the Microbiome in Natural ABO Antibody Production in Mice

et al. 2023

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Background. “Natural” ABO antibodies (Abs) are produced without known exposure to A/B carbohydrate antigens, posing significant risks for hyperacute rejection during ABO-incompatible transplantation. We investigated anti-A "natural" ABO antibodies versus intentionally induced Abs with regard to the need for T-cell help, the impact of sex, and stimulation by the microbiome. Methods. Anti-A was measured by hemagglutination assay of sera from untreated C57BL/6 wild-type (WT) or T cell–deficient mice of both sexes. Human ABO-A reagent blood cell membranes were injected intraperitoneally to induce anti-A Abs. The gut microbiome was eliminated by maintenance of mice in germ-free housing. Results. Compared with WT mice, CD4+ T-cell knockout (KO), major histocompability complex–II KO, and αβ/γδ T-cell receptor KO mice produced much higher levels of anti-A nAbs; females produced dramatically more anti-A nAbs than males, rising substantially with puberty. Sensitization with human ABO-A reagent blood cell membranes did not induce additional anti-A in KO mice, unlike WT. Sex-matched CD4+ T-cell transfer significantly suppressed anti-A nAbs in KO mice and rendered mice responsive to A-sensitization. Even under germ-free conditions, WT mice of several strains produced anti-A nAbs, with significantly higher anti-A nAbs levels in females than males. Conclusions. Anti-A nAbs were produced without T-cell help, without microbiome stimulation, in a sex- and age-dependent manner, suggestive of a role for sex hormones in regulating anti-A nAbs. Although CD4+ T cells were not required for anti-A nAbs, our findings indicate that T cells regulate anti-A nAb production. In contrast to anti-A nAbs, induced anti-A production was T-cell dependent without a sex bias.

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Section: Methodsmentioning

confidence: 99%

Sex, T Cells, and the Microbiome in Natural ABO Antibody Production in Mice

et al. 2023

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Strategies to overcome the ABO barrier in kidney transplantation

et al. 2015

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Kidney transplantation across the ABO blood group barrier was long considered a contraindication for transplantation, but in an effort to increase donor pools, specific regimens for ABO-incompatible (ABOi) transplantation have been developed. These regimens are now widely used as an integral part of the available treatment options. Various desensitization protocols, commonly based on transient depletion of preformed anti-A and/or anti-B antibodies and modulation of B-cell immunity, enable excellent transplant outcomes, even in the long-term. Nevertheless, the molecular mechanisms behind transplant acceptance facilitated by a short course of anti-humoral treatment are still incompletely understood. With the evolution of efficient clinical programmes, tailoring of recipient preconditioning based on individual donor-recipient blood type combinations and the levels of pretransplant anti-A/B antibodies has become possible. In the context of low antibody titres and/or donor A2 phenotype, immunomodulation and/or apheresis might be dispensable. A concern still exists, however, that ABOi kidney transplantation is associated with an increased risk of surgical and infectious complications, partly owing to the effects of extracorporeal treatment and intensified immunosuppression. Nevertheless, a continuous improvement in desensitization strategies, with the aim of minimizing the immunosuppressive burden, might pave the way to clinical outcomes that are comparable to those achieved in ABO-compatible transplantation.

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