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Acquired aplastic anemia (aAA) is an autoimmune disease, characterized by infiltration of T lymphocytes in the bone marrow with destruction of hematopoietic stem cells by the effector cells. Interferon-gamma (IFN-γ) and perforin are important mediators of cell destruction. In this flow cytometry-based study, we have investigated the percentage of intracellular IFN-γ+ and perforin+ CD5+ T cells in peripheral blood of newly diagnosed aAA patients before and after immunosuppressive therapy (IST). Patients were categorized as per standard disease severity and response to IST. The median percentage of IFN-γ+ and perforin+ CD5+ T cells was higher in untreated patients compared to healthy controls. The percentage of these cells was also increased in untreated severe and very severe aplastic anemia when compared with non-severe aplastic anemia patients. In patients before and after IST the median percentage of T cells producing IFN-γ and perforin was elevated in non-responders as compared to partial plus complete responders. The higher percentage of IFN-γ+ and perforin+ CD5+ T cells may be useful as an early diagnostic marker for aberrant activation of immune system and predict poor response to IST in aAA patients, who will benefit from alternative therapy. [ABSTRACT FROM AUTHOR]

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN‐γ, but polyfunctional response including TNF‐α, which is essential for protective granuloma formation. Here, we investigated the impact of PD‐1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD‐1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth (≪CFU) in our in vitro monocyte‐derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α‐PD‐1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD‐1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α‐PD‐1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s). [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world’s population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multidrug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project “In Silico Trial for Tuberculosis Vaccine Development” (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare. Results: We present the application of the Universal Immune System Simulator (UISS) computational modeling infrastructure as a disease model for TB. The model is capable to simulate the main features and dynamics of the immune system activities i.e., the artificial immunity induced by RUTI® vaccine, a polyantigenic liposomal therapeutic vaccine made of fragments of Mycobacterium tuberculosis cells (FCMtb). Based on the available data coming from phase II Clinical Trial in subjects with latent tuberculosis infection treated with RUTI® and isoniazid, we generated simulation scenarios through validated data in order to tune UISS accordingly to STriTuVaD objectives. The first case simulates the establishment of MTB latent chronic infection with some typical granuloma formation; the second scenario deals with a reactivation phase during latent chronic infection; the third represents the latent chronic disease infection scenario during RUT® vaccine administration. Conclusions: The application of this computational modeling strategy helpfully contributes to simulate those mechanisms involved in the early stages and in the progression of tuberculosis infection and to predict how specific therapeutical strategies will act in this scenario. In view of these results, UISS owns the capacity to open the door for a prompt integration of in silico methods within the pipeline of clinical trials, supporting and guiding the testing of treatments in patients affected by tuberculosis. [ABSTRACT FROM AUTHOR]

Containment/dissemination of Leishmaniasis depends on the dominance of Th1/ Th2 immunity. IFN-γ and IL-17A are well known for protection from leishmaniasis. Synergistic effects of these two cytokines are also known in various autoimmune diseases. However, the therapeutic, as well as adjunct therapeutic use of rIL-17A and rIFN-γ in combination with sub-optimal dose of amphotericin-B (AmpB) is still not validated in visceral leishmaniasis. In the present study, we have evaluated the adjunct therapy in a mouse model of VL. After twenty-one days of post infection, in the therapeutic group, mice were intra-peritoneally injected with two doses of recombinant cytokines at one week interval. In adjunct therapeutic groups of mice, immune components were primed for three days with recombinant cytokine(s) followed by injection of sub-optimal dose of AmpB. Body weight, parasitic load in visceral organs and fold change in cytokines' gene expression was evaluated. We observed significant gain in body weight, inhibition of parasitic load in visceral organs {(liver; 71.7% - 95%), (spleen; 70%-88.7%) (Bone marrow; 46.6 -87.1%)}; significant up regulation in fold change of pro-inflammatory cytokine(s) gene expression (TNF-γ,iNOS, IL-2 and IL-12) as well as marginal increase of anti-inflammatory cytokine(s) gene expression (IL-4, IL-10& TGF-γ} in adjunct therapeutic groups of mice. Our results suggest that though the therapeutic use of recombinant cytokine(s) is not the best option; however, use of recombinant cytokine(s) along with suboptimal dose of amphoterocin-B to reduce drug toxicity could have a way for better treatment options. [ABSTRACT FROM AUTHOR]

Background:Natural Killer (NK) cell plays an important role in the innate immune system and is known to produce IFN-γ at an early stage of infection that is essential to eliminate intracellular infection likeLeishmaniaspp. It is already established thatLeishmaniaparasite inhibits the activity of NK cells, avoiding the encounter with the early innate immune response. This, in turn, favors establishment and further dissemination of the infection.Methods:In the present study, we have tried to measure the frequency of different phenotypic subsets of NK cells among visceral leishmaniasis (VL) patients.Results:We have phenotyped three distinct three distinct subsets (CD56–CD161+, CD56+CD161–, and CD56+CD161+) of NK (CD3–) cell using their specific markers CD161 and CD56.Conclusion:Interestingly, we observed selective loss of CD56+CD161+subset of circulating NK (CD3–) cells. Importantly, the other subsets (i.e., CD56−CD161+and CD56+CD161–) of circulating NK cells remain unaffected as compared with healthy subjects. [ABSTRACT FROM PUBLISHER]

CD4+ CD25+ Foxp3+ Regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis--specific IL-10 along with elevation of IFN-c production, and raising the IFN-γ/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients. [ABSTRACT FROM AUTHOR]

The genus Chenopodium is native plant of Western Asia. In Indian traditional literature including Atharva Veda, Rig Veda and Charak Samhita, its various therapeutic and medicinal applications have been mentioned. It has been used for thousands of years in folk medicine in South America, Europe and Brazil for anthelmintic, laxative, diuretic, humoral asthma properties. However, the mode of action is still unclear. Herein, we have evaluated immunomodulatory potential of various extracts of Chenopodium ambrosioides. The immunomodulatory potential was assessed by measuring production of reactive oxygen and nitrogen species on stimulation of PBMCs with different dose of extracts. Activation of macrophage was assessed by stimulating the PBMCs with different doses of the extracts and evaluating the increase in percentage expression of CD86 on macrophages by flow cytometry. Further effect of these extracts on function of macrophages was assessed by production of IL-12 cytokine. It was observed that above said extracts showed significant increase in ROS and NOS production. These extracts also potentially activated the macrophages as evident by increased expression of CD86 on macrophages and further by increased level of IL-12 post stimulation. Chenopodium ambrosiodies has the potential to stimulate the activation of macrophages followed by increased IL-12 production indicating its immunomodulatory significance. [ABSTRACT FROM AUTHOR]

Leukocyte adhesion deficiencies (LADs) are a type of primary immunodeficiencies characterized by delayed detachment of the umbilical cord, impaired wound healing, leukocytosis, and recurrent infections. The disease is caused by genetic defects affecting different steps in the process of leukocyte adhesion cascade such as rolling, integrin activation, and adhesion of leukocytes, resulting in the impairment of leukocyte trafficking. Till date, three types of LAD have been documented: type I, II and III. Type I LAD is caused by congenital defect in the β2 integrin receptor complex CD11/CD18 on the cell surface of leukocytes, which results in impaired leukocytes connection to endothelial cells and migration. Type II LAD is caused by defect in the fucose metabolism resulting in the absence of fucosylated selectin ligands on neutrophils and impaired rolling phase of the leukocyte adhesion cascade. Type III LAD is caused by mutations in the kindlin-3 gene resulting in defective integrin activation. In this article, we present a review of literature for type I LAD, and successful treatment of patient using umbilical cord blood stem cell transplantation. [ABSTRACT FROM AUTHOR]

Abstract: Lipid antigens of Leishmania donovani-like lipophosphoglycans (LPG) are demonstrated to be a potent ligand for natural killer T (NKT) cell activation. Little is known about the phenotype or function of these cells and their trafficking pattern to the bone marrow (BM) of visceral leishmaniasis (VL) patients. Their precise role in humans still requires pathological validation. The study included 42 parasitologically confirmed patients (mean age 24.80±16.26years; range 3–70years; 25 males and 17 females), 33 healthy contact subjects (family/non-family members) and normal BM specimens (NBM; n =9). Enumeration of NKT cells and quantification of parasites (before and after therapy) were performed for the recruited patients. Results established that non-CD1d restricted, diverse cells are the dominant population among resident but not enriched NKT (CD3+CD161+) cells at the disease site (BM). Expression profiles for various markers are indicative of their early activated (CD69+, CD62Llow, CD11ahigh) CCR5+ phenotype at the BM. Functionally, BM-derived NKT cells were dominantly producing IFN-γ in response to L. donovani antigen in vitro. Given these observations, these data indicate that CD3+CD161+ diverse NKT cells are heterogeneous in function and of the dominant Th-1 phenotype at the disease site. [Copyright &y& Elsevier]

Background: Natural Killer (NK) cell plays an important role in the innate immune system and is known to produce IFN-γ at an early stage of infection that is essential to eliminate intracellular infection like Leishmania spp. It is already established that Leishmania parasite inhibits the activity of NK cells, avoiding the encounter with the early innate immune response. This, in turn, favors establishment and further dissemination of the infection., Methods: In the present study, we have tried to measure the frequency of different phenotypic subsets of NK cells among visceral leishmaniasis (VL) patients., Results: We have phenotyped three distinct three distinct subsets (CD56 - CD161 + , CD56 + CD161 - , and CD56 + CD161 + ) of NK (CD3 - ) cell using their specific markers CD161 and CD56., Conclusion: Interestingly, we observed selective loss of CD56 + CD161 + subset of circulating NK (CD3 - ) cells. Importantly, the other subsets (i.e., CD56 - CD161 + and CD56 + CD161 - ) of circulating NK cells remain unaffected as compared with healthy subjects.