Trans-membrane Activator and CAML Interactor (TACI) controls B cell differentiation and memory and exists as numerous allelic variants in healthy individuals. In fact, TACI is among the 5% most polymorphic genes in Man. In mice, dominant negative TACI variants are hypogammaglobulinemic, but can produce bursts of high affinity IgG and clear enteric pathogens faster than the wild type (WT). We asked how TACI variants might impact the outcome of organ transplantation by examining alloimmunity in mice expressing a common human TACI variant that is more frequent in recipients of kidney transplants with antibody-mediated rejection than in non-rejecting subjects.

C57BL/6-BALB/c-F1 hearts were transplanted into either TACI-ko mice (n=17) or WT (n=17) mice. Graft failure was determined by palpation and sections evaluated by H&E and CD4, CD8, FoxP3 and C3d immunohistochemistry. Allo-immunity was also tested in mice expressing a TACI variant (A144E), homologue of a human variant (A181E) found more frequently in recipients of kidney transplants. Alloantibodies were monitored by flow cytometry and by ELISPOT.

TACI-ko mice rejected F1 cardiac allografts faster than WT mice (P=0.01). Cardiac allografts in TACI-ko recipients had increased C3d and more infiltrating CD4+ and CD8+ lymphocytes and less T regulatory cells (CD4+ Foxp3+) early after transplantation than allografts in WT recipients, but had little donor-specific IgM and less donor-specific IgG than WT, consistent with our previous work showing that TACI-ko mice produce little IgM but short bursts of high affinity IgG in response to infectious challenge. To evaluate relevance for clinical transplantation, we monitored alloimmunity in mice expressing a common human TACI variant (mA144E). Homozygous and heterozygous mA144E mice, sensitized by injection of 5×10⁷ BALB/c thymocytes, produced less donor-specific IgG, no donor-specific IgM relative to WT and had increased C3d deposition in the kidneys.

We show that TACI deficiency decreased donor specific humoral response but paradoxically accelerated rejection. Our results suggest that common human TACI variants may pose a risk factor for allograft rejection. Our findings further suggest for the first time that kinetics and diversity of antibody production and isotype might govern the pathogenicity of donor-specific antibodies and accommodation of grafts.

CITATION INFORMATION: Barbosa M., Farkash E., Platt J., Cascalho M. TACI Polymorphisms Associated with Allograft Rejection in Mice and in Man Am J Transplant. 2017;17 (suppl 3).

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