Abstract
Despite its excellent efficacy in controlling T cell mediated acute rejection, lymphocyte depletion may promote a humoral response. While T cell repopulation after depletion has been evaluated in many aspects, the B cell response has not been fully elucidated. We tested the hypothesis that the mechanisms also involve skewed T helper phenotype after lymphocytic depletion. Post-transplant immune response was measured from alemtuzumab treated hCD52Tg cardiac allograft recipients with or without anti-LFA-1 mAb. Alemtuzumab induction promoted serum DSA, allo-B cells, and CAV in humanized CD52 transgenic (hCD52Tg) mice after heterotopic heart transplantation. Additional anti-LFA-1 mAb treatment resulted in reduced DSA (Fold increase 4.75 ± 6.9 vs. 0.7 ± 0.5; p < 0.01), allo-specific B cells (0.07 ± 0.06 vs. 0.006 ± 0.002 %; p < 0.01), neo-intimal hyperplasia (56 ± 14% vs. 23 ± 13%; p < 0.05), arterial disease (77.8 ± 14.2 vs. 25.8 ± 20.1%; p < 0.05), and fibrosis (15 ± 23.3 vs. 4.3 ± 1.65%; p < 0.05) in this alemtuzumab-induced chronic antibody-mediated rejection (CAMR) model. Surprisingly, elevated serum IL-21 levels in alemtuzumab-treated mice was reduced with LFA-1 blockade. In accordance with the increased serum IL-21 level, alemtuzumab treated mice showed hyperplastic germinal center (GC) development, while the supplemental anti-LFA-1 mAb significantly reduced the GC frequency and size. We report that the incomplete T cell depletion inside of the GC leads to a systemic IL-21 dominant milieu with hyperplastic GC formation and CAMR. Conventional immunosuppression, such as tacrolimus and rapamycin, failed to reverse AMR, while co-stimulation blockade with LFA-1 corrected the GC hyperplastic response. The identification of IL-21 driven chronic AMR elucidates a novel mechanism that suggests a therapeutic approach with cytolytic induction.
Highlights
Long-term success of heart transplantation is limited by the development of coronary allograft vasculopathy (CAV), a hallmark of chronic rejection (CR) [1]
We previously reported that alemtuzumab induction prevents acute rejection in humanized CD52 transgenic mice after heterotopic heart transplantation but promotes serum donor-specific antibodies (DSA), allospecific B (allo-B) cells and CAV, making this an applicable model for studying chronic antibody-mediated rejection (CAMR) post cytolytic induction [20]
LFA-1 blockade resulted in significantly reduced allo-B cells in the spleen at post-transplantation day (POD) 100 (Figure 1D)
Summary
Long-term success of heart transplantation is limited by the development of coronary allograft vasculopathy (CAV), a hallmark of chronic rejection (CR) [1] Conventional immunosuppressive strategies, such as CNI inhibitors or rapamycin, that inhibit T cell—mediated rejection do not prevent CR; ∼50% of patients develop biopsy evidence of CAV within 5 years after transplantation [2, 3]. This is a devastating statistic for pediatric transplant recipients because children with organ transplants have the greatest need for long-term graft survival. A lack of satisfactory animal models further hampers progress toward understanding the mechanisms of CAMR
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