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Genetic factors are critical in determining susceptibility to primary biliary cirrhosis (PBC), but there has not been a clear association with human leukocyte antigen (HLA) genes. We performed a multicenter case-control study and analyzed HLA class II DRB1 associations using a large cohort of 664 well-defined cases of PBC and 1992 controls of Italian ancestry. Importantly, healthy controls were rigorously matched not only by age and sex, but also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR), 3.3; 95% confidence interval (CI), 2.4-4.5] and DRB1*02 (OR 0.9; 95% CI 0.8-1.2) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4; 95% CI 0.3-0.4) and DRB1*13 (OR 0.7; 95% CI 0.6-0.9) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. Associated DRB1 alleles were found only in a minority of patients, whereas an additive genetic model is supported by the gene dosage effect for DRB1*11 allele and the interaction of DRB1*11,*13, and *08. Lastly, no significant associations were detected between speci fic DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. In conclusion, we confirm the role for HLA to determine PBC susceptibility and suggest that the effect of HLA is limited to patient subgroups. We suggest that a large whole-genome approach is required to identify further genetic elements contributing to the loss of tolerance in this disease. Copyright © 2008 by the American Association for the Study of Liver Diseases

Cells derived from the amniotic membrane of human placenta have been receiving particular attention because of their stem cell potentiality and immunomodulatory properties, which make them an attractive candidate source for cell therapy approaches. In this study, we isolated cells from the mesenchymal region of amnion and identified two subpopulations discordant for expression of the HLA-DR, CD45, CD14, and CD86 cellular markers. We therefore refer to the unfractionated cell population derived from this region as amniotic mesenchymal tissue cells (AMTC). We studied the suppressive and stimulatory characteristics of the unfractionated, HLA-DR-positive, and HLA-DR-negative AMTC populations and demonstrated that all three fail to induce an allogeneic T-cell response. However, unfractionated AMTC, which could inhibit T-cell allogeneic proliferation responses, induced proliferation of T cells stimulated via the T-cell receptor (TcR), in a cell-cell contact setting. We have shown that this stimulatory capacity can be attributed to the HLA-DR-positive AMTC subpopulation. Indeed, even though the HLA-DR-positive AMTC fraction surprisingly failed to induce proliferation of resting allogeneic T cells, they could cause strong proliferation of anti-CD3-primed allogeneic T cells. This stimulatory effect was not observed using the HLA-DR-negative AMTC fraction. The revelation that human amniotic mesenchyme possesses cell populations with both suppressive and stimulatory properties sheds additional light on the immunomodulatory functions of this tissue and may contribute to the clarification of some ongoing controversies associated with mesenchymal stromal cells of other sources, such as the presence of HLA-DR-positive cells and the suppressive versus stimulatory properties of these cells.

Human tumors constitutively release endosome-derived microvesicles, transporting a broad array of biologically active molecules with potential modulatory effects on different immune cells. Here, we report the first evidence that tumor-released microvesicles alter myeloid cell function by impairing monocyte differentiation into dendritic cells and promoting the generation of a myeloid immunosuppressive cell subset. CD14+ monocytes isolated from healthy donors and differentiated with interleukin (IL)-4 and granulocyte macrophage colony-stimulating factor in the presence of tumor-derived microvesicles turned into HLA-DR(-/low) cells, retaining CD14 expression and failing to up-regulate costimulatory molecules, such as CD80 and CD86. These phenotypic changes were paralleled by a significant release of different cytokines, including IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta (TGF-beta), and a dose-dependent suppressive activity on activated T-cell-proliferation and cytolytic functions, which could be reversed by anti-TGF-beta-neutralizing antibodies. Microvesicles isolated from plasma of advanced melanoma patients, but not from healthy donors, mediated comparable effects on CD14+ monocytes, skewing their differentiation toward CD14+HLA-DR-/low cells with TGF-beta-mediated suppressive activity on T-cell-functions. Interestingly, a subset of TGF-beta-secreting CD14+HLA-DR- cells mediating suppressive activity on T lymphocytes was found to be significantly expanded in peripheral blood of melanoma patients compared with healthy donors. These data suggest the development in cancer patients of an immunosuppressive circuit by which tumors promote the generation of suppressive myeloid cells through the release of circulating microvesicles and without the need for cell-to-cell contact. Therapeutic interventions on the crucial steps of this pathway may contribute to restore tumor/immune system interactions favoring T-cell-mediated control of tumor growt

Background & Aims: This study extends our previously reported observations that various immunological factors are associated with the occurrence of histologically proven recurrent hepatitis C. The two specific issues investigated were to confirm the associations of MHC alleles and donor/recipient mismatch with the occurrence of recurrent hepatitis C in an independent cohort of newly transplanted patients and to look for immunologic and nonimmunologic variables affecting the severity of the recurrent disease. Methods: Two separate cohorts of consecutive patients were studied: a look-back cohort (LC) of 120 patients and a cohort for studying the disease progression (CSDP) of 190 patients. Protocol liver biopsies were obtained at least 1, 3, 5, 7, and 10 years after liver transplantation (LT). Results: A fully mismatched donor/recipient pair at the DRB1 locus was confirmed to be associated with both the recurrence of histologic hepatitis in the LC (59% vs 23%, P = .0002) and its progression beyond stage 3 in the CSPD (71.4% vs 39.3%, P = .0003). Relevant immunologic and nonimmunologic variables were included into a multivariate Cox proportional model and three variables, namely, donor age, full HLA-DRB1 donor-recipient mismatch, and HLA B14, resulted in independent risk factors for the development of severe fibrosis. Conclusion: This study provides evidence that DRB1 donor-recipient mismatch affects both the occurrence and progression of recurrent hepatitis C disease. This information is clinically relevant as it may help to better allocate organs and to recognize patients at risk for progression so that specific interventions can be implemented. © 2006 by the American Gastroenterological Association Institute

Previous studies involving identical twins with concordant leukemia and retrospective scrutiny of archived neonatal blood spots have shown that common chromosome translocations of pediatric leukemia frequently arise before birth. The IGH/TCR clonotypic sequences used as surrogate molecular markers suggest this is also likely to be true for hyperdiploid acute lymphoblastic leukemia (ALL). Yet evidence that hyperdiploidy itself is an early or initiating event occurring prenatally has been limited. Now, however, we can provide direct evidence of this from our identification of CD34+/CD19+ B-lineage progenitor cells with triploid chromosomes in the stored cord blood of an individual who subsequently developed hyperdiploid ALL.

In an attempt to transduce monocyte-derived dendritic cells (DCs) by a retroviral vector coding for a cell surface marker, we were confronted by the observation of high transfer of the surface molecule in the absence of vector proviral DNA in the treated cells. Indeed, DCs acquired the surface marker by a mechanism independent of the vector machinery, requiring cell-to-cell contact and involving transfer of lipids and a variety of intact membrane proteins. Most important, this property of DCs also includes acquisition of foreign human leukocyte antigen (HLA) molecules. Consequently, DCs become immunological hybrids as they display their own and foreign HLA molecules. The newly acquired HLA is fully functional because it allows recognition by allo-specific T lymphocytes and the binding and presentation of antigen peptides.

Transforming growth factor-beta (TGF beta), which is secreted by cultured melanoma cells constitutively, inhibits the proliferation of normal melanocytes and of most melanoma cells in vitro, but some melanoma cells from advanced stages of the disease develop resistance to TGF beta-dependent growth inhibition, without developing any change in TGF beta cell surface binding. In vitro TGF beta also downregulates the expression of HLA-DR molecules on melanoma cells, and upregulates the expression of the beta 3 integrin subunit on some cell lines. Immunohistochemical analysis of 53 melanocytic lesions (12 naevi, 30 primary melanomas and 11 metastases) revealed a trend of increasing expression of TGF beta and TGF beta receptor type III with tumour progression, and a significantly higher expression of both TGF beta (P < 0.0001) and the receptor (P < 0.05) in metastatic and thick (> 1 mm) primary melanomas compared with thin (< 1 mm) primary melanomas. The expression of TGF beta correlated with expression of a marker of proliferation, Ki67, and with HLA-DR and beta 3 integrin subunit expression. Coexpression of the four molecules was observed in all metastases and in most thick primary melanomas. These findings argue against an inhibitory effect of TGF beta on cell proliferation or HLA-DR antigen expression in melanoma, and suggest the upregulation of the beta 3 subunit. TGF beta protein appears to be a biological marker of melanoma progression in situ

A 44-year-old man developed a peripheral neuropathy during treatment with interferon-alpha for chronic hepatitis C. The onset was insidious, beginning symmetrically in the hands with paresthesia. Neurophysiological investigation revealed a predominantly sensory axonal neuropathy. A sural nerve biopsy confirmed primary axonal damage. Immunofluorescence studies showed increased expression of HLA-DR molecules prevalently on Schwann cells of non-myelin-forming type.

Expression of HLA-DR antigens by purified preparations of human ovarian carcinoma cells freshly isolated from surgical specimens was examined in parallel with the capacity of tumor cells to elicit a blastogenic response from autologous lymphocytes in mixed lymphocyte-tumor culture (MLTC) assay. Of 21 tumor preparations, 11 (52%) reacted with monoclonal antibodies 279 and/or 949 specific for a monomorphic determinant of HLA-DR antigens, with heterogeneous positivity, ranging between 30% and 95%. In this series of patients positive MLTC occurred in 8/21 individual experiments. The HLA-DR expression was proportionally similar in tumors giving positive MLTC (4/8 = 50%) and negative MLTC (7/13 = 53%). The lack of correlation between DR expression on tumor cells and stimulatory activity in autologous MLTC and the fact that DR-negative tumors could induce lymphocyte stimulation, support the hypothesis that blastogenesis occurs upon recognition of tumor-associated antigens, different from DR molecules, possibly tumor-specific antigens.