A. Trans-membrane Activator and CAML Interactor (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 laboratory profile, 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. C57BL/6-BALB/c-F1 hearts were transplanted into either TACI deficient (C57BL/6) mice (n=17), or wt (n=17). Alloantibody production was monitored by flow cytometry. Graft failure was determined by palpation and hearts were explanted and evaluated by H&E and immunohistochemistry for CD4, CD8, and C4d. 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=74 alleles) were compared with those with no DSA and normal graft function (N=38 alleles) up to 3 years post-transplant.

C. We found that while 5 out of 13 haplo-identical heart allografts lasted longer than 21 days in TACI-proficient recipients, in TACI-deficient mice, all heart allografts rejected before 21 days (Fisher exact test, P=0.01), suggesting that TACI function controls rejection kinetics. Despite having decreased circulating allo-specific IgG and IgM levels, grafts in TACI-deficient recipients showed increased C4d capillary staining and CD4+ and CD8+ lymphocyte infiltration early after transplantation, consistent with accelerated mixed rejection. In humans, potentially destabilizing polymorphisms in exon 4 (K188M, 2%, A181E, 0.7%, R189M 0.7%.A173P, 0.7%, and G190R, 4.7%) were more common in recipients with persistent de novo antibodies than in controls (K188M, 0.5%, A181E, 0.5%, R189M 0.002%, A173P,0%, and G190R, 1%).

D. Our prior work and these new results 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 probing genetic determinants of the quality of immune responses might offer important clues regarding the outcome of alloimmunity in transplant recipients.

CITATION INFORMATION: Platt J, Farkash E, Lefferts A, Samaniego M, Cascalho M. TACI Polymorphisms Associated with De Novo Alloantibodies in Humans and Allograft Rejection in Mice. Am J Transplant. 2017;17 (suppl 3).

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