Expression of Inhibitory Molecules (Arginase-1, IDO, and PD-L1) by Myeloid-Derived Suppressor Cells in Multiple Myeloma Patients in Remission.

We studied suppressor potential of myeloid-derived suppressor cells (MDSC) in multiple myeloma patients, including before and after mobilization of hematopoietic stem cells (HSC), by evaluating the expression of arginase-1 (Arg1), indolamine-2,3-dioxygenase (IDO), and PD-L1 in MDSC subsets. The study included 20 multiple myeloma patients in remission, 5 patients with progression, as well as 10 sex-and age-matched healthy donors. The expression of Arg1, IDO, and PD-L1 in circulating granulocytic MDSC (G-MDSC, Lin-HLA-DR-CD33+CD66b+), monocytic MDSC (M-MDSC, CD14+HLA-DRlow/-), and early-stage MDSC (E-MDSC, Lin-HLA-DR-CD33+CD66b-) was evaluated by flow cytometry. Multiple myeloma patients in remission were characterized by reduced expression of Arg1 in M-MDSC in comparison with donors. The expression of Arg1 in M-MDSC depended on the number of induction therapy lines performed and was significantly lower in patients who received ⩾2 lines and responded with remission. Patients with multiple myeloma progression (resistant to therapy) showed significantly increased expression of Arg1 and PD-L1 in M-MDSC, as well as increased expression of Arg1 in E-MDSC. After G-CSF-induced mobilization of HSC, the content of circulating Arg1-expressing M-MDSC increased significantly. Considering the presence of MDSC in apheresis products, MDSC suppressive activity is discussed as a factor affecting the outcomes of autologous HSC transplantation in multiple myeloma patients.

[Diagnosis and treatment of aquired aplastic anemia].

AIM: To analyse the results of diagnosis and treatment of patients with aquired aplastic anemia (AA) in one center. MATERIAL AND METHODS: All AA patients, diagnosed and treated in one clinic in 1998-2005, were included in the trial. In severe and very severe AA (SAA/VSAA) the patients (n = 19) received combined immunosuppressive therapy (IST) with antithymocytic globulin (ATG) and cyclosporin A (CsA), in non-severe AA (NSAA) the patients (n = 9) were given monotherapy with CsA. Allogenic transplantation of bone marrow (alloTBM) was made in 4 young patients with SAA/VSAA. RESULTS: The diagnosis of AA was established in 33 patients (19 males and 14 females): NSAA in 9, SAA in 19, VSAA in 5, idiopathic--in 26, posthepatic--in 5, associated with pregnancy--in 2 patients. Age median was 20 years (13-53). The clone of paroxysmal nocturnal hemoglobinuria (PNH) was identified in 7 of 33 patients (21%), antigen HLA-DRB1 *15 in 6 of 11 patients (55%). In median of 26-month follow-up 31 patients (94%) were alive. In IST, complete or partial remissions were obtained in 88% patients. Median of the interval to achievement of transfusion independence made up 2.5 months. All the patients after alloTBM are in complete remission, chronic extensive transplant against host reaction was observed in one case. CONCLUSION: Introduction of updated protocols provides long-term survival of more than 80% AA patients. To optimize treatment outcomes, it is necessary to include newly diagnosed AA patients into ongoing multicenter studies.

Cytokine-producing activity of bone marrow erythrokaryocytes and its regulation under normal conditions.

We showed that inhibition of cytokine production by bone marrow adherent cells and their soluble products is a mechanism of regulation of cytokine-producing activity of bone marrow erythrokaryocytes under normal conditions.

High-dose immunosuppression with autologous stem cell transplantation in severe refractory systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an immune-mediated disease that is responsive to suppression or modulation of the immune system. Patients with SLE who experience persistent multiorgan dysfunction, despite standard doses of intravenous cyclophosphamide (Cy), represent a subset of patients at high risk of early death. We investigated the efficacy and toxicity of high-dose immunosuppression and autologous hematopoietic stem cell transplantation (SCT) to treat such patients. Six patients (all female, age 15-29 years) with severe refractory SLE were enrolled in the clinic of our institution from 1998 to 2003. All patients were seriously ill, with SLE disease activity indices (SLEDAI) of 6-30, including two cases with central nervous system lupus, one case with lung vasculitis, and three cases with nephritis and nephrotic syndrome. All patients were registered in the European Group for Blood and Marrow Transplantation (EBMT)/European League Against Rheumatism (EULAR) database. Previous immunosuppression included pulse Cy intravenous, prednisolone (standard doses and pulse therapy), oral Cy and azathioprine, with little or no effect on disease progression. Autologous hemopoietic stem cells were collected from bone marrow (n = 4) or mobilized from peripheral blood with Cy and granulocyte colony-stimulating factor (G-CSF) (n = 2). Pre-transplant conditioning regimens included BEAM +/- ATG (n = 2), melphalan 140 mg/m2 + etoposid 1600 mg/m2 (n = 2) and Cy 200 mg/kg +/- ATG (n = 2). Median time to an absolute neutrophil count (ANC) greater than 0.5 x 10(9)/L and platelet count greater than 50 x 10(9)/L was 13 and 15 days, respectively. Three patients died on days 11, 22 and 63 due to transplant-related complications. The follow-up is now 60 and six months for two patients (complete remission), and 42 months for one other patient (partial response). All patients had experienced multiple and severe episodes of infections pre-SCT and long-term history of corticosteroid therapy (3-14 years). We conclude that achievement of prolonged, corticosteroid-free remissions is a reality. Judicious selection of patients earlier in disease or in remission, but with a high risk of relapse or further progression, will diminish transplantation-related mortality.