Differences in Protein Secretion by Multipotent Mesenchymal Stromal Cells Effective and Ineffective in the Prevention of Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Multipotent mesenchymal stromal cells (MSC) were administered to patients after allogeneic hematopoietic stem cell transplantation to prevent the development of acute graft-versus- host disease (GVHD). The injection of MSC did not always prevent the development of GVHD. The aim of the work was to compare the secretome of MSC effective and ineffective in the prevention of GVHD. MSC were obtained from the bone marrow of hematopoietic stem cells donors. The secretome was studied using a TripleTOF 5600+ mass spectrometer with a NanoSpray III ion source coupled to a NanoLC Ultra 2D Plus nano-HPLC System. A total of 1,965 proteins were analyzed. Analysis of the secretome of effective and ineffective MSC samples revealed significant differences in the secretion of 1,119 proteins associated with ribosomes, exosomes, focal contacts, and others. Analysis of proteins secreted by MSC can be used to identify prognostically effective samples.

Individual Differences of Multipotent Mesenchymal Stromal Cells Manifesting in during Interaction with Lymphocytes.

Analysis of changes in lymphocyte subpopulations during co-culturing with multipotent mesenchymal stromal cells (MSC) revealed two distinct MSC groups: one group (A) increased HLA-DR expression on lymphocytes during co-culturing and the other (B) did not change it in comparison with lymphocyte monoculture. In stromal cells interacting with lymphocytes, expression of HLA-DR molecules was initiated, but only in samples that induced enhanced expression on lymphocytes and irrespectively of whether allogeneic or autologous lymphocytes were used for co-culturing with MSC. In group A, the relative expression of IDO1 significantly increased in comparison with group B. The revealed individual differences in MSC can explain why not all MSC samples are effective in the treatment of autoimmune diseases, acute "graft-versus-host" disease, and other pathologies.

Co-Culturing of Multipotent Mesenchymal Stromal Cells with Autological and Allogenic Lymphocytes.

We studied the effect of autologous and allogeneic lymphocytes on multipotent mesenchymal stromal cells in co-culture. It is shown that changes in multipotent mesenchymal stromal cells and in lymphocytes did not depend on the source of lymphocytes. Contact with lymphocytes triggers expression of HLA-DR molecules on multipotent mesenchymal stromal cells and these cells lose their immune privilege. In multipotent mesenchymal stromal cells, the relative level of expression of factors involved in immunomodulation (IDO1, PTGES, and IL-6) and expression of adhesion molecule ICAM1 increased, while expression of genes involved in the differentiation of multipotent mesenchymal stromal cells remained unchanged. Priming of multipotent mesenchymal stromal cells with IFN did not affect these changes. In turn, lymphocytes underwent activation, expression of HLA-DR increased, subpopulation composition of lymphocytes changed towards the increase in the content of naïve T cells. These findings are important for cell therapy.

[Adult B-cell acute lymphoblastic leukemias: Conclusions of the Russian prospective multicenter study ALL-2009]. / Ostrye V-limfoblastnye leikozy vzroslykh: vyvody iz Rossiiskogo prospektivnogo mnogotsentrovogo issledovaniia OLL-2009.

AIM: To analyze the efficiency and reproducibility of the ALL-2009 protocol within the Russian prospective multicenter study based on different principles of cytostatic effects (non-intensive, but continuous cytotoxic treatment and a small number of allogeneic hematopoietic stem cells). SUBJECTS AND METHODS: The ALL-2009 (NCT01193933) study conducted in April 2009 to December 2016 included 194 patients (95 males and 99 females) aged 15 to 55 years (median age 28 years) with Ph-negative B-cell acute lymphoblastic leukemia (ALL). There was early pre-B-cell ALL in 54 patients, common ALL in 101, pre-B ALL in 39, initial leukocytosis in 9.4·109/l (0.4-899.0), lactate dehydrogenase in 901 IU (31-13 059), an initial central nervous system lesion in 17 (8.7%), mediastinal injury in 3 (1.5%), and splenomegaly in 111 (57.2%). The results of standard cytogenetic analysis are known in 113 (60.4%) patients. Normal karyotypes were detected in 49 (54.5%) out of the patients; t(4;11) in 9 (5.4%), t(1;19) in 2 (1.2%), and other karyotypic abnormalities in 53 (46.9%). Thirteen (7.8%) patients underwent allogeneic hematopoietic stem cell transplantation in first complete remission (CR); their proportion did not differ in the federal and regional centers. RESULTS: The frequency of CR achievement was the same in the federal and regional centers and generally amounted to 87.5%. Early (8.8%) and CR (9.6%) mortality rates remained high despite the low aggressiveness of cytotoxic action, necessitating the improvement of auxiliary treatment. The five-year overall survival (OS) rates vary considerably in the federal and regional centers (72.6 and 43.8%), the relapse-free survival (RFS) (70.2 and 53.4%) and recurrence risk (23.1 and 36.5%) are comparable. This suggests that the non-intensive, but continuous exposure principle built in the ALL-2009 protocol makes it possible to reproduce the envisaged treatment program and to achieve satisfactory results. CONCLUSION: The ALL-2009 protocol allows both the federal and regional centers to obtain the long-term results comparable with those of current foreign studies: OS (54.2%), RFS (56.5%); and relapse risk (35.4%). Multivariate analysis has identified age (over 30 years), initial leukocytosis (30·109/l and more) and t(4;11) among the main clinical prognostic factors. Gene mutation detection evaluated in a small number of patients (8/36) is not a poor prognostic sign. There is a need for further investigations with centralized evaluation of the mutation status of leukemic cells and the clearance of minimal residual disease.

Changing the Properties of Multipotent Mesenchymal Stromal Cells by IFNγ Administration.

We studied changes in the population of human multipotent mesenchymal stromal cells activated by IFNγ. The cells were cultured under standard conditions; IFNγ was added in various concentrations for 4 h or over 2 passages. It was shown that the total cell production significantly decreased after long-term culturing with IFNγ, but 4-h exposure did not affect this parameter. After 4-h culturing, the expression levels of IDO1, CSF1, and IL-6 increased by 300, 7, and 2.4 times, respectively, and this increase persisted 1 and 2 days after removal of IFNγ from the culture medium. The expression of class I and II MHC (HLA) on cell surface practically did not change immediately after exposure to IFNγ, but during further culturing, HLA-ABC (MHC I) and HLA-DR (MHC II) expression significantly increased, which abolished the immune privilege in these cells, the property allowing clinical use of allogenic multipotent mesenchymal stromal cells. Multipotent mesenchymal stromal cells can suppress proliferation of lymphocytes. The degree of this suppression depends on individual properties of multipotent mesenchymal stromal cell donor. Treatment with IFNγ did not significantly affect the intensity of inhibition of lymphocyte proliferation by these cells.

[Russian experts' clinical guidelines for acute myeloid leukemia treatment in patients less than 60 years of age].

The purpose of the paper is to present Russian experts' consolidated opinion about acute myeloid leukemia (AML) treatment in adult patients aged less than 60 years. The guidelines have been elaborated having regard to foreign publications and Russian experience, on the basis of global and Russian clinical trials to treat AML and to define indications for allogeneic bone marrow transplantation in patients during first complete remission.

[Treating patients with acute myeloid leukemias (AML) according to the protocol of the AML-01.10 Russian multicenter randomized trial: the coordinating center's results].

AIM: To make a randomized comparison of 2 consolidation treatment options (two patient groups): 2 cycles of cytarabine in average (Ig/m2 in Group 2) and standard (100 mg/mi2 in Group 1) doses in combination with idarubicin (8-12 mg/m2) and mitoxantrone (10 mg/m2), after two 7+3 induction cycles of daunorubicin (60 mg/mi2) and subsequent 6 cycles of maintenance therapy. SUBJECTS AND METHODS: In January 2010 to October 2013, a Russian multicenter trial was conducted to treat patients with acute myeloid leukemias (AML) in accordance with the AML-01.10 protocol (ClinicalTrials.gov Identifier: NCT01587430). The trial enrolled 243 AML patients from 21 centers, including 71 patients (median age 38 years) from the State Hematology Center, Ministry of Health of the Russian Federation; 35 and 36 patients were randomized to Groups 1 and 2, respectively. The randomized groups were balanced by basic clinical and laboratory parameters. Favorable, intermediate, and high cytogenetic prognoses were in 14 (21.9%), 40 (62.5%), and 10 (15.6%) patients, respectively. RESULTS: Prior to treatment, 2 patients died; one patient refused treatment. Fifty-eight (85.3%) of the 68 patients achieved complete remission (CR); early deaths was in 2 (2.9%) and resistance in 8 (11.8%). Four (6.9%) patients died during CR. Protocol deviations (doses, intervals, and the number of cycles) were recorded in 12 (20.7%) of the 58 patients. Other 8 (11.8%) patients were switched to low-dose cytarabine because of complications, withdrawn from the protocol and not included into the analysis of randomized comparison. Twenty allogeneic bone marrow transplantations (allo-BMT) (7 related, 12 unrelated, and 1 haploidentical) were performed; of them 15 allo-BMTs were done during first CR. In the 68 patients, 3-year overall survival (OS) was 45.6%; relapse-free survival (RFS) was 41.5%. OS was 64.6% in Group 1 and 58.3% in Group 2; RFS was 62 and 38.8% in Groups 1 and 2, respectively (p>0.5). In the favorable, intermediate, and high prognosis groups, OS was 79.5, 60, and 31.1% and RFS was 81.8, 41.3, and 33.3%, respectively (p=0.1). The consolidation treatment option unchanged survival rates in the above risk groups. Unachieved CR after the first cycle considerably decreased RFS (33.9% versus 60%) and served as an indication for allo-BMT during first CP (RFS without BMT was 0; that with BMT was 78%). CONCLUSION: No differences were found between both consolidation options according to long-term results. Protocol deviations were recorded in one-third of the patients. While implementing the protocol, the efficiency of treatment was high. Allo-BMT during first CR substantially increased RFS if CP was not achieved after the first cycle.

[Selection of an unrelated donor for hematopoietic stem cell transplantation. HLA haplotypes in patients with blood system diseases].

AIM: To study the distribution of HLA-A*-B*-C*-DRB1 *-DQB1 * haplotypes in patients with blood system diseases, to establish the most common HLA haplotypes, and to compare the findings with the data on the frequency and distribution of the highest-frequency HLA haplotypes in donors of a number of leading registries. SUBJECTS AND METHODS: In 2008-2012, the Hematology Research Center, Ministry of Health of the Russian Federation, examined 203 patients with blood system diseases who needed allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their 386 blood relatives. Typing ascertained the kind of HLA haplotype in all the patients. Among the patients, there were 97 men who were aged 17 to 64 years (median 38 years) and 106 women who were aged 18 to 59 years (median 40 years). RESULTS: The examinees were found to have 265 different HLA haplotypes. There were 21 high-frequency HLA haplotypes; of them 7 belonged to 10 HLA haplotypes that are most frequent in the representatives of the Caucasoid race. Nearly 30% of the patients who needed allo-HSCT and had no HLA-identical siblings had HLA haplotypes out of the 10 ones that are most common in the representatives of the Caucasoids and thus could expect to find a compatible unrelated donor for a short time. The examinees were found to have a wide variety of HLA haplotypes (265 types in 203 persons). This variety, as well as the extreme polymorphism of HLA alleles, shows that there should be large registries of HLA-typed bone marrow donors in the country. These registries increase the chance to find a HLA-compatible unrelated donor for a short time for a patient with blood disease who has an indication for hematopoietic stem cell transplantation. The performed study supported that there were regional features in the distribution of HLA haplotypes within the same ethnic group. CONCLUSION: The chance to find a HLA-compatible donor for Russian patients in the large national registry that accumulates donors from different regional populations is substantially higher than that in the foreign registries. To create large cohorts of HLA-typic bone marrow donors from different regions of the country will substantially increase the chance of patients with blood system diseases to find a HLA-compatible unrelated donor.

[Successful treatment of a patient with two hematologic tumors: double-hit lymphoma and acute myelomonoblastic leukemia].

Double-hit (DH) lymphoma, an extremely aggressive variant of B-cell lymphoma, is accompanied by chromosomal abnormalities leading to the activation of a few oncogenes, one of which is the c-MYC gene in conjunction with BCL2 or BCL6 gene rearrangements. There are most common cases of MYC/8q24 and BCL2/18q21 gene rearrangements (MYC/BCL-2 DH lymphoma). The tumor is characterized by an aggressive clinical course and a poor response to chemotherapy (CT). The median survival in patients with DH lymphomas varies from 4.5 to 18 months. Such patients are generally resistant to CHOP-21 and R-CHOP-21 therapy regimens. For the treatment of patients with DH lymphoma, the Hematology Research Center, Ministry of Health of the Russian Federation, chose an original BL-M-04 polychemotherapy (PCT) protocol in combination with rituximab, followed by autologous stem cell transplantation (allo-SCT). The paper describes the experience in successfully treating a patient with two hematologic tumors: 1) MYC/BCL-2 DH lymphoma with high-dose PCT cycles, followed by allo-SCT, and 2) a metachronously developed second tumor (acute myelomonoblastic leukemia (AMML)) with CT cycles, followed by auto-SCT. The incidence of tumors induced by the previous high-dose CT for aggressive lymphomas for 10 years is 0.7 to 10%. As a rule, the development of secondary AMML is preceded by a history of myelodysplastic syndrome (MDS); characteristic chromosomal abnormalities (deletions of the long arm of chromosomes 5 and 7) are detectable. In this case, the follow-up was 3 months before the development of AMML, during this period the patient was not found to have laboratory signs of MDS (anemia, thrombocytopenia) or chromosomal abnormalities associated with secondary MDS/AML. The presence of a leukemic stem cell is associated with the occurrence and development of hemoblastosis; that of the similar cell populations that may cause B-cell lymphomas remains uncertain. The described case may have defect in a hematopoietic stem cell that gives rise to both germs of hematopoiesis, as well as complete donor chimerism of bone marrow hematopoiesis, which gives hope to long-term remission in both DH lymphoma and AMML.

[Treatment of adult patients with acute promyelocytic leukemia according to the AIDA protocol].

AIM: To give the results of an investigation conducted at the Hematology Research Center (HRC), Ministry of Health of the Russian Federation (MHRF), to treat adult patients with acute promyelocytic leukemia (APL) according to the AIDA protocol elaborated by Spanish investigators. SUBJECTS AND METHODS: The investigation enrolled 33 patients diagnosed with APL verified by cytogenetic and molecular studies, who had been treated at the HRC, MHRF, in July 2009 to January 2012. The patients classified in the low-, intermediate-, and high-risk groups were 30, 46.7; and 23.3%, respectively. The analysis was made in January 2013. RESULTS: The number of patients who achieved complete remission, as well as the mortality rates during remission induction were wholly comparable to those previously obtained when using the 7+3+ATRA protocol: 90.3 and 9.7%, respectively. One patient in remission died (3.6% mortality rate). The likelihood of recurrence in this investigation was high (21%), which was due to gross noncompliance with maintenance therapy. On examining the clearance of the malignant clone by FISH and polymerase chain reaction, a naturally chimeric transcript identified by a molecular study was statistically significantly more frequently revealed during postinduction therapy, which was associated with different sensitivity of the techniques. Comparison of changes in the disappearance of a chimeric marker for APL with the AIDA and 7+3+ARTA programs showed that the clearance of the malignant clone was much slower. CONCLUSION: The AIDA program is a highly effective treatment protocol for patients with APL.

[Successful use of vemurafenib in a patient with resistant hairy cell leukemia].

The paper describes a case of a patient with refractory hairy cell leukemia. In spite of the absence of CD25 expression, the disease was classified as a classical form according to the WHO classification (2008), as also confirmed by the detection of BRAFV600E mutation. The disease was characterized by resistance to all lines of therapy (interferon-a, splenectomy, cladribin). Clinical and hematological remission was achieved within 2 months of administration of the BRAF kinase inhibitor vemurafenib.

[Efficiency of treatment of adult patients with acute T-lymphoblastic leukemia according to the ALL-2009 protocol of the Russian Acute Leukemia Study Group].

AIM: To present the results of treatment in adult patients with acute T-lymphoblastic leukemia (T-ALL) according to the ALL-2009 protocol of the Russian Acute Leukemia Study Group, the basic principle of which is continuation of cytostatic treatment, early switch from prednisolone to dexamethasone, and long-term use of L-asparaginase. SUBJECTS AND METHODS: The results of diagnosis and treatment were analyzed in 70 patients with different immunological variants of T-ALL treated in the Russian multicenter trial. RESULTS: Out of the 70 patients with T-ALL, its early immunotype was determined in 32 (45.7%) cases, the thymic and mature immunotypes were found in 31 (44.3%) and 7 (10%) cases, respectively. The median age of the patients with T-ALL was 28 (ranged from 15 to 54) years; men were twice more than women (48 and 22, respectively). Bone marrow lesion was noted in all the patients with early T-ALL and in 80% of the patients with thymic and mature T-ALL. The enlarged mediastinum was significantly more frequently detected in mature T-ALL (100%) than in its early (53.4%) and thymic (60.7%) variants. Therapeutic effectiveness was evaluated in 58 patients. An analysis was made in January 2013. Induction therapy resulted in complete remission in 49 (84.5%) patients. The refractory course of the disease was recorded in 5 (8.6%) cases; early death was in 4 (6.9%). The rate of complete remission in thymic T-ALL, unlike in the early (72%) and mature (71.4%) variants, was significantly higher (100%) due to the absence of resistant forms and early mortality. Moreover, it should be noted that only the patients with early T-ALL (16%) died during the induction phase. In the patients with different variants of T-ALL, the overall and relapse-free survival rates were not significantly different, accounting for 67.2 and 76.2%, respectively. Multivariate analysis revealed no prognostically unfavorable factors that determined long-term results. CONCLUSION: The ALL-2009 protocol is reproducible in any regions of the Russian Federation and highly efficient in treating patients with T-ALL.

[Characteristics of stromal cell precursors in patients after allogeneic bone marrow transplantation].

UNLABELLED: AIM. To study the elements of the mesenchymal stromal cell compartment (multipotent mesenchymal stromal cells (MMSCs)) and their more mature progenies of fibroblast colony-forming units (CFU-F) in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). SUBJECTS AND METHODS. The total production of MMSCs after 5 passages, the time of their growth, and the concentration of CFU-F in the bone marrow from patients were determined using the control sections before transplantation and over time for 2 years after allo-HSCT. What is more, the genetic affiliation of the MMSCs from the patients after allo-HSCT and their immunophenotype were studied. RESULTS: The MMSCs from the patients after allo-HSCT belong to a recipient and have the immunophenotype that meets the international standard for these cells. The total production of MMSCs in the cultures obtained from the bone marrow of the patients with hematologic diseases was decreased. Not all the samples from the patients after allo-HSCT are able to undergo 5 passages. In addition, the time of growth substantially increases and the total production of cells decreases in all the analyzed cultures. These indicators are gradually restored; however, they never achieve the mean values in donors. The concentration of CFU-F in the bone marrow from the patients are reduced as compared to that in the donors prior to transplantation and decreased still further after allo-HSCT. These cell precursors are not restored for at least 2 years following allo-HSCT. CONCLUSION. Both examined categories of the cell precursors of the stromal environment suffer from both the disease itself and allo-HSCT in the patients with hematologic diseases.

[The first results of treatment for adult acute myeloid leukemia according to the AML-01.10 protocol of the Research Group of the Hematology Centers of Russia].

AIM: To give the preliminary results of the AML-01.10 Russian multicenter randomized trial to treat adult acute myeloid leukemia (AML), the basic principle of which is to use high-dose anthracycline antibiotics in induction/consolidation. SUBJECTS AND METHODS: By December 2011, 145 patients with AML had been randomized from 18 hematology centers of 15 cities and towns of the Russian Federation; the median age of all the patients was 44 years. Seventy-one patients were analyzed in August 2011 (a 1.5-year follow-up). RESULTS: The efficiency of 2 courses 7+3 using high-dose daunorubicin (60 mg/m2 per administration) and continuous infusion of cytarabine during the second course was high and comparable with that in the use of a high-dose HAM protocol as a second induction course and can achieve a complete remission in 74.6%. The protocol toxicity evaluated from its early mortality (11.3%) and its death in complete remission (16.6%) was permissible, particularly by taking into consideration the multicenter pattern of the trial. At the completion of analysis, 53 (68.8%) out of the 77 patients on whom the data on their vital status were available were alive. In this follow-up period, the frequency of recurrences was 19.2% (10/52). Only 3 (4.2%) patients out of the 71 patients in whom the efficiency of the protocol had been completely evaluated underwent allogeneic bone marrow transplantation. CONCLUSION: The total high dose (720 mg/m2) of anthracycline antibiotics, which is used in the period of induction and consolidation, determines the long periods of myelosuppression and intercourse intervals. Protocol deviations (no course of consolidation therapy, lower-dose idarubicin during consolidation therapy, a course of low-dose cytarabine, between the courses of induction and consolidation chemotherapy, and very long intercourse intervals) were recorded in a total of 20 (28%) patients.

[Treatment of acute host-versus-graft reaction in patients after allogeneic hematopoietic cell transplantation with multipotent mesenchymal stromal cells from a bone marrow donor].

AIM: To evaluate the efficiency of administration of multipotent mesenchymal stromal cells obtained from a bone marrow donor for the treatment of an acute host-versus-graft reaction (HVGR) resistant to therapy with glucocorticosteroids (GCS). SUBJECTS AND METHODS: The experience in treating 6 patients with GCS-resistant acute HVGR following allogeneic hematopoietic stem cell transplantation is given. The patients were intravenously injected cultured multipotent mesenchymal stromal cells (MMSC) in a dose of 10(6) per kg body weight. RESULTS: Four weeks after MMSC administration, a complete or partial response was obtained in 3 cases; clinical improvement was noted in 2; one patient showed no response. MMSC therapy proved to be effective in 5 of the 6 cases with acute HVGR resistant to GCS therapy. CONCLUSION: MMSC therapy turned out to be effective in case of acute HVGR resistant to GCS therapy.

[Effect of bortezomib on the efficiency of hematopoietic stem cell mobilization in patients with multiple myeloma].

AIM: To study the results of mobilizing and collecting autologous hematopoietic stem cells (HSC) in patients with multiple myeloma (MM) receiving bortezomib as part of induction therapy regimens. MATERIALS AND METHODS: In June 2001 to April 2010, the Department of Bone Marrow Transplantation, Hematology Research Center, Ministry of Health and Social Development of Russia, mobilized autologous HSC in 93 patients with MM, by using cyclophosphan (CF) and granulocyte colony-stimulating factor. The analysis covered 73 patients who received VAD and/or bortezomib-containing courses as induction therapy. Group 1 comprised 30 patients whose induction therapy was performed as 3-4 courses of VAD. Group 2 included 19 patients who had 2-4 courses of PAD or 4-8 courses of bortezomib + dexamethasone in addition to 1-3 courses of VAD. Group 3 combined 24 patients who used 6-8 courses of bortezomib + dexamethasone or 3-4 courses of PAD + 4-6 courses of bortezomib + dexamethasone. RESULTS: In Group 1 patients whose induction therapy was performed as 3-4 courses of VAD, baseline peripheral blood CD34+ cell counts were 3,575 +/- 631 in 1 ml, which was statistically significantly higher than those in Group 2 patients who had bortezomib-containing courses in addition to VAD courses. In Group 2 patients, premobilization CD34+ cell counts were 2,164 +/- 516 in 1 ml. The lowest blood CD34+ cell levels (1,586 -/+ 405 in 1 ml) were observed in Group 3 patients in whom bortezomib was used as first-line therapy. In Group 1 patients, the maximum peripheral blood counts of CD34+ cells were 322,287 +/- 73,994 in 1 ml, which was significantly higher than their maximum level in Groups 2 (231,624 +/- 39,708 in 1 ml) and 3 (161,007 +/- 44,266 in 1 ml) patients. The efficiency of mobilization proved to be high; more than 4.0.10(6)/kg of CD34+ cells were collected in all the patients with bortezomib-containing induction therapy, which allowed two autologous HSC transplantations to be carried out. CONCLUSION: Adding bortezomib at the stage of induction has no significant impact on the results of HSC mobilization and collection. By taking into account the possibility of achieving a complete or very good partial response in 40-60% of the patients using the bortezomib-containing regimens as first-line therapy, bortezomib should be considered as an essential drug as part of induction therapy.

Analysis of expression of genes involved in immune response modulation in silent multipotent mesenchymal stromal cells.

The expression of some genes modulating the immune response was studied in multipotent mesenchymal stromal cells (MMSC) from the bone marrow of a healthy donor. Non-activated MMSC expressed IL-6 and IL-10, complement H factor, macrophage growth factor, prostaglandin E2 synthase, and indoleamine-2,3-dioxygenase. The expression of all these genes was higher in female MMSC. A close inverse relationship between IL-6 expression in MMSC and male donor age, close relationship between body weight index and fibroblast CFU concentration in female donor bone marrow and between indoleamine-2,3-dioxygenase and macrophage growth factor in MMSC from these donors were detected. The expression of the analyzed genes was higher in MMSC of donors who had no antibodies to cytomegalovirus, herpes simplex virus, and Epstein-Barr virus in the blood. The results demonstrate the MMSC regulation of immune reactions by MMSC at the cell and organism levels.

[Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience)].

AIM: To analyse results of transplantation of allogenic and autologous hemopoietic stem cells (allo-THSC and auto-THSC) with myeloablation preconditioning in patients with acute leukemia (AL) performed in 1987-2006. MATERIAL AND METHODS: A total of 71 allogenic and 45 autologous THSC were performed in 116 patients with different AL variants. Conditioning in all allo-THSC included busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). This regimen was used in 29 recipients of auto-HSC. Cyclophosphamide in a dose 120 mg/kg and total radiation of the body in a dose 12 Gy were given to 16 recipients. Overall, relapse-free and event-free survival of patients after THSC were analysed as well as early (first 100 days) and overall lethality. Auto-THSC in 15 patients was for the first time followed by immunomodulating therapy aimed at prevention of AL relapses: in acute myeloid leukemia ATRA in combination with alpha-interferon, in acute lymphoblastic leukemia (ALL)--ronkoleukin, interleukin-2 preparation. RESULTS: Overall survival of AL patients after allo-THSC for the observation period increased from 31 to 58%, early lethality fell from 44 to 4%. Results of allo-THSC conducted in the first complete remission were much better than in patients with other AL stages at the time of THSC. After auto-THSC 5-year survival rose from 22 to 60% while early lethality reduced from 33 to 4%. Administration of immunomodulating therapy after auto-THSC increases 5-year survival from 35 to 80%. CONCLUSION: Outcomes of THSC in AL has improved for the last 20 years. Outcomes of allo-THSC performed in the first complete remission are much higher. Immunomodulating therapy after auto-THSC promoted better results.

[Allogenic bone marrow transplantation in chronic myeloid leukemias]. / Transplantatsiia allogennogo kostnogo mozga pri khronicheskom mieloleikoze.

AIM: To assess the role of allogenic bone marrow (ABM) transplantation in chronic myeloid leukemia (CML). MATERIAL AND METHODS: 44 ABM transplantations were performed in 37 CML patients in the chronic phase and 7 patients in acceleration or blast crisis. RESULTS: A complete molecular remission was achieved in 26 (59%) patients: 67.6% after ABM transplantation in the chronic phase and only 14.3% after myelotransplantation in non-chronic phase. Follow-up was 8-150 months (median--59 months). Early lethality after ABM transplantation in the chronic phase was under 14%. A phase of the disease plays a key role in ABM transplantation. If it is made in a chronic phase, CML recurrence rate is low (in our series it was 14%), efficacy of donor's bone marrow lymphocyte transfusions is high. The second complete molecular remission was achieved in 3 of 4 cases of posttransplantation recurrences. Probability of maintenance of a complete remission after ABM transplantation in a chronic phase was 75%, recurrence-free survival--64%, uneventful survival 55% for 90 months. CONCLUSION: The experience of many years demonstrates high efficacy of ABM transplantation in the treatment of chronic myeloid leukemia. It promotes long-term molecular remission the maintenance of which did not require therapy in 65% patients.

[Use of the multi-component VP-4 vaccine to prevent acute respiratory diseases at preschool children's establishments]. / Isopol'zovanie polikomponentnoi vaktsiny VP-4 dlia profilaktiki ostrykh respiratornykh zabolevanii v detskikh doshkol'nykh uchrezhdeniiakh.

The multicomponent VP-4 vaccine from Klebsiella pneumonia, Staphyloccocus aureus, Proteus vulgaris, Escherichia coli antigens was used to prevent acute respiratory diseases (ARD) at preschoolchildren's establishments. Prevention was effected during an influenza epidemic with a drastic rise in the incidence of ARD. The VP-4 use involved 3 nasal and 6-9 oral administrations of the drug at an interval of 3-4 days. The duration of the course was 26 +/- 4 days. The preventive action of VP-4 on the incidence of ARD was followed up for 14 months after vaccination. One group comprised 89 vaccinated children, a matched group included 69 children whose age was 2 to 6 years. Immunoprophylaxis was found to promote a reduction in the number of children who had 4 ARD episodes or more during the whole follow-up. Administration of VP-4 prevented the development of repeated episodes ARD in a group of children aged 2-3 years and in frequently ill children who had 3 infections or more in the previous year. The slight reactogenicity of the drug and its long-term preventive effect allow this method of immunoprophylaxis to be recommended for frequently ill children, for those at high risk, and for those in the junior age group (under 4 years) before going to preschoolchildren's establishments.