Induction of Donor-Specific Immune Hypo-Responsiveness Across Major Histocompatibility Complex Barriers in Murine Models of Solid Organ Transplant: Repurposing Extracorporeal Photochemotherapy

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient’s own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex (MHC) mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

Effect of Ethyl Acetate Fraction of Marsilea crenata Presl. Leaf Extract on Major Histocompatibility Complex Class II Expression in Microglial HMC3 Cell Lines

Phytoestrogens are plant-derived chemical substances that have estrogen-like structures or estrogenic functions. Deficiency of estrogen in human brain causes neuroinflammation characterized by increase of major histocompatibility complex class II (MHC II) expression as a marker of M1 phenotype in microglia. Recent research found phytoestrogen compounds in Marsilea crenata Presl. The aim of this study was to investigate the effect of ethyl acetate fraction of Marsilea crenata Presl. leaf extract in MHC II expression of microglial HMC3 cell lines, for resolution of inflammation and tissue repair. The fractions were given at concentrations of 62.5, 125, and 250 ppm to microglia, that had been previously induced by IFNγ 10 ng for 24 hours to stimulate the cells into M1 phenotype. Genistein as phytoestrogen was given at a concentration of 50 μM as positive control. Expression of MHC II was analyzed using immunocytochemistry method. Result showed reduction in MHC II expression of microglial cells, which indicated the activity of all extracts and, showed that 250 ppm of the fraction showed the strongest effect with MHC II value expression of 148.632 AU, and ED50 of 1,590 ppm. It was concluded from the study, that ethyl acetate fraction of Marsilea crenata Presl. leaves has antineuroinflammation effect.

Fine-Mapping of the Major Histocompatibility Complex Region Linked to Leprosy in Northern China

Background: Leprosy is a chronic infectious skin and neurological disease, and genetic background is considered to be one of the major factors of risk. The major histocompatibility complex (MHC) region not only affects susceptibility to leprosy but also its development and outcome. Given the complex traits of the MHC region, variants and the potential mechanism by which HLA influences leprosy development need to be further explored.Methods: We extracted previous genome-wide association study data from the Northern Han Chinese population to perform HLA fine-mapping. Using the 1,000 Genome Project Phase 3 dataset as the reference panel, single-nucleotide polymorphisms (SNP), insertion and deletion (INDEL) and copy number variant (CNV) imputation were carried out. HLA classical alleles and amino acids in the MHC region were imputed using the HAN-MHC database. Further stepwise regression analysis was conducted to analyze independent signals of variants related to leprosy.Results: We identified four independent variants: esv3608598, rs7754498, rs3130781 and rs144388449. Among them, esv3608598 is a CNV and the first HLA CNV associated with leprosy risk. SNP annotation using RegulomeDB, HaploReg, and rVarBase showed that three SNPs are likely to affect the pathogenesis of leprosy.Conclusion: In summary, this is the first study to assess the association between HLA CNV and leprosy susceptibility in a Northern Han Chinese population. By fine mapping of the MHC region in this population, our findings provide evidence for the contribution of HLA to leprosy susceptibility.

Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study)

BackgroundThis study aimed to evaluate the antitumor activity of camrelizumab, an antiprogrammed cell death-1 antibody, in pretreated recurrent or metastatic nasopharyngeal carcinoma (NPC) and to explore predictive biomarkers.MethodsPatients with recurrent (not amenable to locally curative treatment) or metastatic NPC who had failed at least two lines of chemotherapy were eligible to receive camrelizumab (200 mg intravenously every 2 weeks) for 2 years or until disease progression, intolerable adverse events, withdrawal of consents, or investigator decision. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Programmed cell death-ligand 1 (PD-L1) expression was assessed by immunohistochemistry. Other immune-related biomarkers including major histocompatibility complex class I and major histocompatibility complex class II (MHC-II) were assessed by multiplex immunofluorescence staining.ResultsBetween August 14, 2018, and December 30, 2019, a total of 156 patients were enrolled. The IRC-assessed ORR was 28.2% (95% CI 21.3% to 36.0%). The median progression-free survival was 3.7 months (95% CI 2.0 to 4.1) per IRC, and the median overall survival was 17.4 months (95% CI 15.2 to 21.9). The ORRs were 35.2% (95% CI 25.3% to 46.1%) vs 19.4% (95% CI 10.4% to 31.4%) in patients with tumor PD-L1 expression of ≥10% and<10%, respectively. Patients with durable clinical benefit (DCB), which was defined as complete response, partial response or stable disease of ≥18 weeks, had higher density of MHC-II+ cell in stroma than patients without DCB (median 868.1 (IQR 413.4–2854.0) cells/mm2 vs median 552.4 (IQR 258.4 to 1242.1) cells/mm2). MHC-II+ cell density did not correlate with PD-L1 expression, and a composite of high stromal MHC-II+ cell density and tumor PD-L1 expression further enriched patients who could benefit from camrelizumab.ConclusionsCamrelizumab had clinically meaningful antitumor activity in patients with recurrent or metastatic NPC. The composition of both MHC-II+ cell density and PD-L1 expression could result in better patient selection.

Deeplearning based MHC epitope prediction for cancer neoantigen discovery

Neoantigens are important for cancer immunotherapies or cancer vaccine development, but identification of neoantigens is challenging. The high binding affinity between the mutated peptide and MHC (major histocompatibility complex) molecules of the patients is a necessary factor for a somatic mutation on the tumor genome to form a neoantigen. MHC epitope prediction tools can be used for the identification of neoantigens. This research investigates MHC epitope prediction by utilizing Tri-peptide similarity as features for the XGBoost classifier. This model was tested on experimentally validated cancer neoantigen peptides.