*Purpose: Transmembrane activator and CAML interactor (TACI) controls B cell differentiation. The TACI gene is highly polymorphic (>95% of all genes) and frequently variants exhibit a dominant-negative phenotype. People and mice with TACI variants have low baseline levels of Ig. However, TACI-deficient mice produce bursts of high affinity IgG evidently protective against certain pathogens. We hypothesized that individuals with TACI dominant negative variants or TACI-deficiency mount allogenic responses of greater pathogenicity.

*Methods: To determine whether and how TACI polymorphisms might impact on allogeneic responses, we immunized C57BL/6 mice harboring (a) mono-allelic mA144E (murine homologue of human A181E dominant negative phenotype); (b) bi-allelic mA144E; (c) TACI-KO; and (d) WT with BALB/c thymocytes and splenocytes and compared the alloantibody and B cell responses. To determine how impact on graft outcome, we performed heterotopic cardiac transplants from C57BL/6-BALB/c-F1 into C57BL/6 TACI-KO and WT mice and compared kinetics of rejection, pathology of the grafts and alloantibody levels. We investigated response to immunization to avoid as much as possible confounding effect of Ab absorption to grafts.

*Results: Immunization of C57BL/6 mice with mono or bi-allelic (mA144E) TACI variants and TACI-KO produced little or no allo-specific IgM and significantly less allo-specific IgG than WT mice (p<0.01). Likewise, TACI-KO mice had less allo-IgG than WT after heterotopic cardiac transplantation. Nevertheless, TACI-KO mice rejected cardiac allografts faster than WT (p<0.05). Cardiac allografts in TACI-KO mice had increased IgG and C3d and increased infiltration by CD4 and CD8⁺ cells, but fewer T regulatory cells. Differences in alloimmune responses and graft outcome were explained at least in part by differences in gene expression examined 10 days after immunization in germinal center B cells, as TACI-deficient mice had decreased Xbp1, Mzb1, Foxp3, Ndfip1, Ighm, Fcna, regulating Ig production; and C6, C1qa, C1qb, C1qc and increased C1ra expression regulating complement activation.

*Conclusions: TACI variants govern allogeneic responses by limiting natural IgM and supporting sudden IgG production that heightens complement activation. Although total allo-specific IgG is not appreciably changed, the manner of production has profound impact on pathogenicity. Our results thus suggest that presence of certain TACI variants in a graft recipient may increase the likelihood that an alloimmune response that arises will cause pathology of the graft. The present results suggest for the first time that kinetics, isotype and diversity of allo-antibody might govern the pathogenicity of donor-specific antibodies and accommodation of grafts.

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