Introduction: Graft-versus-host disease (GVHD) is frequent and fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT) and characteristically involves skin, gut, and liver. Macrophages promote tissue regeneration and mediate immunomodulation. Macrophages are divided into two different phenotypes, classically activated M1 (pro-inflammatory or immunereactive macrophages) and alternatively activated M2 (anti-inflammatory or immune-suppressive macrophages). The anti-inflammatory effect of M2 macrophage led us to test its effect in the pathophysiology of GVHD. Methods: GVHD was induced in lethally irradiated BALB/c mice. M2 macrophages derived from donor bone marrow (BM) were administered intravenously, while controls received donor BM-mononuclear cells and splenocytes. Animals were monitored for clinical GVHD and analyzed.Results: We confirmed that administering donor BM-derived M2 macrophages attenuated GVHD severity and prolonged survival after HSCT. Moreover, donor BM-derived M2 macrophages significantly suppressed donor T cell proliferation by cell-to-cell contact in vitro. Conclusions: We showed the protective effects of donor-derived M2 macrophages on GVHD and improved survival in a model of HSCT. Our data suggest that donor-derived M2 macrophages offer the potential for cell-based therapy to treat GVHD.

Acute lymphoblastic leukemia (ALL) is the most common malignant disorder in children and intensive combination therapy has markedly improved patient prognosis. However, efficacy of the treatment still fails in 10-15% of patients. Glucocorticoids (GCs) such as prednisone and dexamethasone (DEX) are essential drugs used for ALL chemotherapy, and the response to GC treatment is a strong independent factor of ALL prognosis. In the present study, we examined the mechanism of GC resistance of B-cell precursor ALL (BCP-ALL). As determined by RT-qPCR and western blot analyses, GC treatment upregulated glucocorticoid receptor (GR) protein and Bcl-2-interacting mediator of cell death (BCL2L11, BIM) protein expression, resulting in apoptosis of a GC-sensitive BCP-ALL cell line, but not of a GC-resistant BCP-ALL cell line as shown by flow cytometry. GR was downregulated in a DEX-resistant BCP-ALL cell line which was induced by treatment of cells with increasing concentrations of DEX. Importantly, expression levels of miR-142-3p and miR-17~92 cluster were upregulated in the BCP-ALL cell line with acquired DEX resistance as examined by RT-qPCR. Our results suggest that interference of miR-142-3p and miR-17~92 may overcome the resistance of BCP-ALL to GCs.

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B-1a cells are distinguishable from conventional B cells, which are designated B-2 cells, on the basis of their developmental origin, surface marker expression, and functions. In addition to the unique expression of the CD5 antigen, B-1a cells are characterized by the expression level of CD23. Although B-1a cells are considered to be independent of T cells and produce natural autoantibodies that induce the clinical manifestations of autoimmune diseases, there is much debate on the role of B-1a cells in the development of autoimmune diseases. We examined the involvement of B-1a cells in autoimmune-prone mice with the lpr gene. MRL/lpr and B6/lpr mice exhibited lupus and lymphoproliferative syndromes because of the massive accumulation of CD3+CD4-CD8-B220+ T cells. Interestingly, the B220+CD23-CD5+ (B-1a) cell population in the peripheral blood and peritoneal cavity increased with age and disease progression. Ninety percent of B-1a cells were CD3 positive (CD3+ B-1a cells) and did not produce tumor necrosis factor alpha, interferon gamma, or interleukin-10. To test the possible involvement of CD3+ B-1a cells in autoimmune disease, we tried to eliminate the peripheral cells by hypotonic shock through repeated intraperitoneal injections of distilled water. The fraction of peritoneal CD3+ B-1a cells decreased, and symptoms of the autoimmune disease were much milder in the distilled water-treated MRL/lpr mice. These results suggest that CD3+ B-1a cells could be mediators of disease progression in autoimmune-prone mice.

This case involved a 27-year-old man with extreme obesity (body mass index 45.6 kg/m 2 ) who had a history of fulminant hepatitis and living-donor liver transplantation at 11 years of age. He had been receiving oral sustained-release tacrolimus (TAC) 1.5 mg daily, and the trough concentration in the blood was below 2.0 ng/mL. He has an intrinsic cytochrome P450 3A5 (CYP3A5)*3/*3 (G/G) genotype and graft liver with CYP3A5*3 allele donated by his biological father. Additionally, there were no data on the phenotype of P-glycoprotein. He did not take medications, grapefruit, or St. John's wort, which interact with CYP3A4 and P-glycoprotein. He intentionally took 30 mg of TAC and presented with symptoms of general malaise and poisoning. On the day of hospitalization (day 0), TAC was discontinued due to an elevated blood TAC concentration of > 60 ng/mL. Additionally, the blood TAC concentration exceeded 10 ng/mL for more than 3 days. He exhibited mild elevation of alanine aminotransferase, aspartate aminotransferase, and creatinine phosphokinase without apparent clinical symptoms. After discharge, blood TAC concentration decreased to 7.4 and 3.7 ng/mL on days 14 and 28, respectively, from the day of excessive TAC intake. Finally, the blood TAC concentration fell below 2.0 ng/mL on day 66. This case report showed that extreme obesity and the liver CYP3A5*3 allele delayed the elimination of TAC after excessive intake of the drug.