Autoantibodies against perlecan/LG3 fragment (anti-LG3) have been associated with accelerated allograft rejection and long-term renal allograft dysfunction. Intriguingly, anti-LG3 are present prior to transplantation in patients that had neither allosensitizing conditions nor classic autoimmune diseases. Here, we sought to understand the mechanisms responsible for immunization to LG3 prior to transplantation to identify targets of intervention.

Wild type (WT) C57BL/6 mice and CD4+ T cell depleted mice (CD4 dep) were immunized with recombinant murine LG3, mouse serum albumin (MSA) or PBS every 2 weeks for a total of 4 immunizations in the presence or absence of incomplete Freund's adjuvant (IFA). WT mice with established anti-LG3 production were depleted of CD4+ T cells by weekly injections of anti-mouse CD4 (i.p:100 [mu]g/injection). Anti-LG3 IgG, total IgG and anti-nuclear antibodies (ANA) titers were assessed by ELISA every week until sacrifice. Circulating anti-LG3 levels were evaluated immediately prior to transplantation and one month post-transplantation in 33 de novo human renal transplant recipients that receive calcineurin inhibitor based immunosuppression (CNIbI) which are T cell targeting agents.

LG3 immunization triggered anti-LG3 production even in the absence of IFA (LG3+IFA 25/25; 100%, LG3 w/o IFA: 14/34; 41%) suggesting that inflammation is not a prerequisite for production of anti-LG3 antibodies. LG3 immunization did not modulate total IgG levels nor ANA concentration indicating that anti-LG3 production is not the consequence of a broad autoimmune response. MSA immunization did not induce anti-LG3 production showing that break in tolerance to LG3 is specific to LG3 immunization. CD4dep mice immunized with LG3 failed to develop anti-LG3 antibodies demonstrating the pivotal role of CD4+T cells in mediating humoral responses to LG3. In human renal transplant recipients a significant decrease in anti-LG3 titers (p<0.01) was observed upon initiation of CNI-based immunosuppression concurring to an important role for CD4 T cells in controlling anti-LG3 production. In mice that already had established anti-LG3 production, CD4 depletion significantly decreased anti-LG3 titers compared to non depleted mice (p<0.01) .

Collectively, these results identify T cells as target of interventions for decreasing deleterious anti-LG3 levels prior to transplantation.

CITATION INFORMATION: Dieudé M., Padet L., Karakeussian-Rimbaud A., Yang B., Turgeon J., Cardinal H., Hébert M-.J. Identification of T Cells as Target of Intervention to Decrease Anti-LG3 Autoantibody Levels Prior to Transplantation Am J Transplant. 2017;17 (suppl 3).

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