Dendritic cells are responsible for the capacity of CpG oligodeoxynucleotides to act as an adjuvant for protective vaccine immunity against Leishmania major in mice

Vaccination with leishmanial Ag and CpG oligodeoxynucleotides (ODN) confers sustained cellular immunity and protection to infectious challenge up to 6 mo after immunization. To define the cellular mechanism by which CpG ODN mediate their adjuvant effects in vivo, the functional capacity of distinct dendritic cell (DC) subsets was assessed in the lymph nodes (LNs) of BALB/c mice, 36 h after immunization with the leishmanial antigen (LACK) and CpG ODN. After this immunization, there was a striking decrease in the frequency of the CD11c+B220+ plasmacytoid DCs with a proportionate increase in CD11c+CD8-B220- cells. CD11c+CD8+B220- cells were the most potent producers of interleukin (IL)-12 p70 and interferon (IFN)-gamma, while plasmacytoid DCs were the only subset capable of secreting IFN-alpha. In terms of antigen presenting capacity, plasmacytoid DCs were far less efficient compared with the other DC subsets. To certify that DCs were responsible for effective vaccination, we isolated CD11c+ and CD11c- cells 36 h after immunization and used such cells to elicit protective immunity after adoptive transfer in naive, Leishmania major susceptible BALB/c mice. CD11c+ cells but not 10-fold higher numbers of CD11c- cells from such immunized mice mediated protection. Therefore, the combination of LACK antigen and CpG ODN adjuvant leads to the presence of CD11c+ DCs in the draining LN that are capable of vaccinating naive mice in the absence of further antigen or adjuvant.     

Heterogeneity of memory B cells

Potential solid organ transplant recipients broadly sensitized to HLA have long wait times, low transplant rates and poor outcomes. The new kidney allocation system has improved access to the most highly sensitized recipients; however, their long‐term outcomes are unknown. Emerging data suggest that memory B cell repertoire is broader than the plasma cell repertoire, therefore, despite refinements in anti‐HLA antibody detection technology, donor‐specific HLA‐ specific memory B cells may in fact be present in some, if not most, highly sensitized recipients with no detectable donor‐specific antibodies. In addition, new findings have underscored the heterogeneity in memory B cell generation, and in the signals that determine memory versus plasma cell fate during primary antigen encounter, as well as memory B cell differentiation upon antigen reencounter into plasma cells or reentry into germinal centers to subsequently emerge as higher affinity and class‐switched plasma cells. Thus, heterogeneity memory B cells generation may affect the efficacy of specific immunomodulation during the recall response. We propose that the ability to quantify donor‐specific B cell in transplant recipients is urgently required to provide insights into the mechanisms of sensitization and recall, and for the early detection of acute and chronic AMR.     

Dopamine D2 receptor agonists inhibit lung cancer progression by reducing angiogenesis and tumor infiltrating myeloid derived suppressor cells

We sought to determine whether Dopamine D2 Receptor (D2R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D2R agonist therapy. We demonstrate D2R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D2R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D2R in lung endothelium. Our results suggest D2R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D2R expression and a smoking history.     

Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.     

The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model

T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1-specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1-specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients. Subtherapeutic doses of rapamycin plus TIM-1-specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1-specific antibody. Importantly, CD4(+)CD25(+) Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4(+)CD25(+) Tregs. Consistent with this, TIM-1-specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.     

Genetic polymorphism of Y-chromosomal STRs in Gujjar population of Punjab

Y-STR polymorphism of Gujjar population was determined by using AmpFISTR®YfilerTM PCR amplification kit. A total 176 haplotypes were obtained after the analysis of 17 Y-STR loci in 176 genetically unrelated individuals. Haplotype diversity and discrimination capacity attained was 0.99730 and 0.652201325, respectively. The comparison of Gujjar population with 16 other populations revealed that Gujjars have low genetic distance from Punjabi, Sindhi, and Pakhtun population of Pakistan; Azad Kashmir, Saraswat Brahmin from India; Bangladeshi population; north and south of Afghanistan; and Uttar Pradesh India which hints toward the migrational route Gujjars took over the centuries. This data is of significant value for population studies and forensic applications.     

Significant bronchospasm during sickle cell painful crises is associated with a lower peripheral eosinophil count

BACKGROUND: Bronchial hyperresponsiveness and/or bronchospasm are recognized complications of sickle cell disease. OBJECTIVE: The aim of this study was to investigate the presence of bronchospasm during painful crises, using simple spirometry in patients with sickle cell disease. METHODS: A prospective, non-randomized study was undertaken in patients with homozygous sickle cell disease, who presented with increasing pain. A painful crisis was defined as any increase in bodily pains necessitating hospital admission. A 15% increase in FEV(1) following salbutamol nebulization was considered significant. RESULTS: Thirty-nine patients took part in the study. Significant bronchodilator responses were demonstrable in 48.7% of patients during painful crises. Patients with such a response had a significantly lower peripheral blood eosinophil count (mean count 0.17 x 10(9)/L vs. 0.445 x 10(9)/L, P = 0.02, confidence interval for difference between groups, 0.0, 0.39). Furthermore, the magnitudes of the bronchodilator responses were related to the degree of lowering of peripheral blood eosinophil counts (r(s) = -0.344, P = 0.037). CONCLUSION: Significant bronchospasm is demonstrable in a sizeable proportion of patients presenting with painful sickle cell crises. There seems to be a negative correlation between the magnitude of bronchospasm and the peripheral blood eosinophil count. We postulate a possible role for pulmonary sequestration of eosinophils in the pathophysiology of bronchospasm in sickle cell disease patients.     

IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma

Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in most grade 2 and 3 gliomas, secondary glioblastomas, and a subset of acute myelogenous leukemias but have not been detected in other tumor types. The mutations occur at specific arginine residues and result in the acquisition of a novel enzymatic activity that converts 2-oxoglutarate to D-2-hydroxyglutarate. This study reports IDH1 and IDH2 genotyping results from a set of lymphomas, which included a large set of peripheral T-cell lymphomas. IDH2 mutations were identified in approximately 20% of angioimmunoblastic T-cell lymphomas (AITLs), but not in other peripheral T-cell lymphoma entities. These results were confirmed in an independent set of AITL patients, where the IDH2 mutation rate was approximately 45%. This is the second common genetic lesion identified in AITL after TET2 and extends the number of neoplastic diseases where IDH1 and IDH2 mutations may play a role.     

Bloom Syndrome in Two Siblings

Abstract: Bloom syndrome (congenital telangiectatic erythema) is a rare autosomal recessive disorder characterized by telangiectasias and photosensitivity, growth deficiency of prenatal onset, variable degrees of immunodeficiency, and increased susceptibility to neoplasms of many sites and types. We are reporting Bloom syndrome in two brothers from Kashmir (India), 8 and 6 years of age, who presented with erythematous rashes on the face, photosensitivity, and growth retardation.