No abstract

Biomarker surveillance after solid organ transplant is an advancing field with promise for further elucidation through high-throughput analyses and "omics" technologies. To date, Gene Expression Profiling (GEP; AlloMap  ) is the only FDA-cleared genomic assay as surveillance for moderate-severe TCMR versus allograft quiescence after heart transplantation. Clinical validity and utility, however, have been recently established after kidney and heart transplantation, for analysis of donor-derived cell-free DNA in the assessment for potential "Allograft Tissue Injury" that may occur during diverse processes such as T-Lymphocyte mediated (TCMR) or Antibody-mediated (ABMR) allograft rejection or allograft-associated infection. These genomic analytes are currently being explored and

Introduction: TH-17 and IL-6 interactions and detrimental biologic effects have been shown in rodent models of Chronic Lung Allograft Dysfunction (CLAD). Similarly, these pathways have been found to be upregulated in human CLAD. Tocilizumab (TCZ), a humanized monoclonal antibody targets the IL-6 receptor subunit alpha and prevents binding of IL-6. We herein report our preliminary experience with adjunctive TCZ therapy for human CLAD. Methods: We retrospectively reviewed our initial experience with TCZ given after other immunotherapies for CLAD. Linear Regression Slopes for Forced Expiratory Volume-1 sec (FEV-1/Month) (L/month), infection incidence, Single Antigen Flow Cytometry HLA Class I & II Donor-specific antibodies (DSA), Non-HLA Auto-antibodies (EC-1 & 2; AT1R) and adverse events. Results: Nine LT recipients with CLAD Stages: BOS I (N=2), BOS II (N=4), BOS III (N=2), RAS (N=1) who received > 3 months treatment with TCZ (4-8 mg/Kg/month intravenous) in combination with Rabbit ATG (N=5), Rituximab (N=1) and IVIG (N=9) were analyzed. Median FEV-1/Month Slope PRE-therapy was-0.132+0.148 L/month and for POST-era this was-0.012+0.049 (P=0.011). HLA DSA Class I & II decreased in 75% LT recipients while Non-HLA antibodies were unaffected by these therapies. Respiratory viral infection (N=2) and fatal cardiac event (N=1) occurred in this cohort. Conclusion: Combination Sequential Immune modulation using Tocilizumab for CLAD after LT can ameliorate the Spirometric decline and would be appropriate for further Multi-Center, controlled clinical trials based on our knowledge of allo-immunologic pathobiology and these pilot human data.