Disease relevant HLA class II alleles isolated by genotypic, haplotypic, and sequence analysis in North American Caucasians with pemphigus vulgaris.

Early studies of genetic susceptibility to pemphigus vulgaris (PV) showed associations between human leukocyte antigen (HLA) DR4 and DR6 and disease. The emergence of DNA sequencing techniques has implicated numerous DRB1 and DQB1 loci in various populations, leading to confusion regarding which exact alleles confer susceptibility. The strong linkage disequilibrium among DR and DQ HLA alleles further complicates the investigation of the true susceptibility loci. In this study, we report genotyping data for the largest sampling of North American Caucasian non-Jewish and Ashkenazi Jewish PV patients studied to date and compare our data with other population studies. To pinpoint true susceptibility, alleles among overrepresented sequences, we applied a step-wise reductionist analysis through (1) determination of the degree of linkage disequilibrium (LD) between purportedly associated alleles, (2) haplotype frequencies comparisons, and (3) primary sequence comparisons of disease-associated versus non-disease-associated alleles to identify crucial differences in amino acid residues in putative peptide binding pockets. Collectively, our data provide extended support for the hypothesis that the HLA associations in Caucasian PV patients map to DRB1*0402 and DQB1*0503 alone. Further structure-function studies will be required to define the exact mechanisms of HLA-mediated control of susceptibility and resistance to disease.

Intravenous immunoglobulin and thymoglobulin facilitate kidney transplantation in complement-dependent cytotoxicity B-cell and flow cytometry T- or B-cell crossmatch-positive patients.

BACKGROUND: The aim of this study was to investigate the effect of Thymoglobulin and intravenous immunoglobulin (i.v.IG) therapy on the clinical outcome of a putatively high-risk group of kidney transplant recipients who have positive B-cell complement-dependent cytotoxicity (CDC) along with positive T- or B-cell flow cytometry (FC) crossmatch results. METHODS: We prospectively studied the effects of i.v.IG and Thymoglobulin induction treatment in B-cell CDC, and T- or B-cell FC crossmatch-positive kidney transplant recipients (seven women and one man; mean age, 43+/-12 years). RESULTS: Mean peak panel-reactive antibody (PRA) was 47+/-32. Three patients had donor-specific antibody by flow PRA (two anti-DR4 and one anti-A2). Each recipient received induction treatment with i.v.IG 100 mg/kg for 3 days and Thymoglobulin 1.5 mg/kg for 5 days after transplantation. No acute cellular rejections occurred during a median follow-up of 15 months (range, 12-17 months). Only one acute humoral rejection occurred 8 days after transplantation, which responded to plasmapheresis, i.v.IG, and rituximab. One allograft was lost because of polyoma nephritis. Patient survival was 100% and allograft survival was 88%. CONCLUSION: Our results indicate that i.v.IG and Thymoglobulin induction treatment may facilitate kidney transplantation in B-cell CDC and T- or B-cell FC crossmatch-positive patients.

Unresectable squamous cell carcinoma of donor origin treated with immunosuppression withdrawal and liver retransplantation.

Posttransplantation allograft malignancy of donor origin is a rare complication after liver transplantation. In the case described, subjective fevers and nonspecific abdominal complaints nearly 6 months following cadaveric liver transplantation in a young woman prompted an evaluation which was remarkable for a large central liver mass. A poorly differentiated squamous cell carcinoma was diagnosed, but was unresectable at exploration. The tumor was confined to the liver. Histocompatibility testing using polymerase chain reaction (PCR) amplification techniques identified both donor and recipient HLA alleles. The patient was treated with chemoembolization, systemic chemotherapy and cessation of immunosuppression. Repeat biopsy 2 months later showed the tumor to be completely necrotic. With decompensated liver disease, she was relisted and retransplanted. More than 2 years later she remains disease-free with complete pathological remission. This is the only reported case of squamous cell carcinoma of donor origin arising in a transplanted liver.