A. Trans-membrane Activator and CAML Interactor (TACI) gene is among the 5% most polymorphic genes in humans, TACI controls B cell differentiation and memory and exists as numerous allelic variants among healthy individuals and individuals with Common Variable Immunodeficiency (CVID). In mice, dominant negative TACI variants have a CVID-like phenotype, but show increased antibody affinity and enteric pathogen clearance. We asked whether TACI variants might impact the alloimmune response and outcome of organ transplantation.

B. In a cohort of human renal transplant recipients, TACI coding regions in those with persistent de novo donor specific antibodies (DSA) with or without biopsy-proven antibody mediated rejection (AMR, n=198 alleles) were compared with those with no DSA and normal graft function (N=114 alleles) up to 3 years post-transplant and to the frequencies found in >120,000 alleles sequenced by the ExAC consortium.

C. We found that potentially destabilizing polymorphisms in exons 4 and 5 were more common in recipients with persistent de novo antibodies and AMR than in the general population (A173P, 0.7% vs none in ExAC, A181E, 1% vs 0.5% in ExAC, K188M, 2.5% vs 0.5% in ExAC, R189M 0.7%. vs 0.0.001% in ExAC, and G190R, 0.7% vs 0.003% in ExAC). Consistent with the idea that some alleles are associated with AMR, we found certain TACI variants were underrepresented in subjects with good outcomes, possibly with accommodation. Those alleles were V220A (2% in AMR vs 0.01% in non-rejecting controls), P251L (6% in AMR vs 0.05% in non-rejecting controls), and T234M (33.3% in AMR vs 0.3% in non-rejecting controls). Preliminary analysis of donor-specific antibody responses and single donor-specific B cell Ig (heavy and light chain) sequencing revealed that one rejecting subject expressing a G190R TACI variant produced highly mutated donor-specific Ig compared to recipients with healthy grafts (p<0.0001) many months before rejection.

D. Our work presented here and our prior observations suggest a working hypothesis that would explain the high prevalence of TACI polymorphisms among healthy individuals and the functional implications of common variants in transplantation. Our findings also suggest that TACI variants might determine the quality of immune responses to transplantation and in this way offer important clues regarding the pathogenicity of alloimmunity in transplant recipients.

CITATION INFORMATION: Cascalho M., Barbosa M., Farkash E., Platt J. Accommodation and Antibody Mediated Rejection Are Associated with Distinct TACI Polymorphisms in Kidney Transplant Recipients Am J Transplant. 2017;17 (suppl 3).

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