PD-1 deficiency augments bone marrow failure in a minor-histocompatibility antigen mismatch lymphocyte infusion model

Although PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life-threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1-deficient (PD-1 knockout [KO]) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe bone marrow (BM) hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN-infused mice relative to mice that received B6 LN cell infusion. Mice that received PD-1 KO LN cells had more CD8+ T-cell infiltration of the BM and greater expansion of H60-specific CD8+ T cells than did their B6 LN-infused counterparts. In the spleen, CD8+ T cells were skewed to an effector memory phenotype, suggesting accelerated differentiation of PD-1 KO T cells. Our data suggest that PD-1 dysregulation has a role in murine BM failure and vigilance in irAE monitoring may be desirable to treat early AA and related cytopenias

Chlorella pyrenoidosa mediated lipid production using Malaysian agricultural wastewater: effects of photon and carbon

Light and carbon being the vital ingredients of photosynthetic reactions can be exploited for algal culture productivity and yield enhancement to effectively treat wastewater by significantly reducing the presence of organic and inorganic compounds. This communication reports the photon flux (light intensity) and glucose (C6H12O6) concentration (as carbon source) dependent improvement of the biomass and lipid production in Chlorella pyrenoidosa (CP) microalgae abundant in Malaysian palm oil mill sewage. Cultures having density 150 mol.m−2 s−1 are grown under varying light flux and temperature. Evaluations of algal productivity are made for three light cycles (ratio of h in light to dark) such as 24:0, 16:8, and 8:16. CP culture with continuous illumination (24:0) produced highest lipid content of 17 mg. Conversely, two other cycles (16:8 and 8:16) yielded 13.10 and 9.43 mg, respectively. The CP growth efficacy of palm oil mill effluent (POME) and subsequent drop in nutrients is demonstrated. Furthermore, the specific growth rate with light is observed to be comparable to the one achieved via C6H12O6 mediated growth. Production of CP for the biomass and lipid generation is optimized using 5 L batch culture grown for 2 weeks duration, where amounts of biomass as high as 0.68 gL−1 d−1 mgCDW−1 is achieved. However, 250 mL batch culture grown for 4 weeks generated a maximum biomass of 0.009 gL−1 d−1 mgCDW−1. The gradual reduction (after 2 days) of organic carbon and nutrients in the culture is attributed to the usage of carbon source mediated microalgae growth and subsequent lipid production. Eventually, CP manifested the removal of organic carbon amounts to 34, 65, and 47 % with the carbon per total nitrogen (C/TN) ratio of 100:7, 100:13, and 100:32, respectively. It is established that POME (as carbon enriched media) assisted enhanced CP growth under illumination can considerably reduce the presence of organic and inorganic compounds

Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failure

Interleukin-18 (IL-18), also known as interferon-gamma (IFN-γ)-inducing factor, is involved in Th1 responses and regulation of immunity. Accumulating evidence implicates IL-18 in autoimmune diseases, but little is known of its role in acquired aplastic anemia (AA), the immune-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). IL-18 protein levels were significantly elevated in sera of severe AA (SAA) patients, including both responders and nonresponders assayed before treatment, and decreased after treatment. IL-18 receptor (IL-18R) was expressed on HSPCs. Co-culture of human BM CD34 + cells from healthy donors with IL-18 upregulated genes in the helper T-cell and Notch signaling pathways and downregulated genes in the cell cycle regulation, telomerase, and IL-6 signaling pathways. Plasma IL-18 levels were also elevated in murine models of immune-mediated BM failure. However, deletion of IL-18 in donor lymph node cells or deletions of either IL-18 or IL-18R in recipients did not attenuate elevations of circulating IFN-γ tumor necrosis factor-alpha, or IL-6, nor did they alleviate BM failure. In summary, our findings suggest that, although increased circulating IL-18 is a feature of SAA, it may reflect an aberrant immune response but be dispensable to the pathogenesis of AA