GM-CSF Promotes the Expansion and Differentiation of Cord Blood Myeloid-Derived Suppressor Cells, Which Attenuate Xenogeneic Graft-vs.-Host Disease

Myeloid-derived suppressor cells (MDSCs) are increased in tumor patients. Studies have shown generation of MDSCs from human peripheral blood mononuclear cells (PBMCs) by various cytokine combinations. However, large scale expansion of human MDSCs has not been demonstrated or applied in clinic settings. We investigated which cytokine combinations among GM-CSF/SCF, G-CSF/SCF, or M-CSF/SCF efficiently expand and differentiate human MDSCs following culture CD34+ cells of umbilical cord blood (CB). GM-CSF/SCF showed the greatest expansion of MDSCs. Up to 108 MDSCs (HLA-DRlowCD11b+CD33+) could be produced from 1 unit of CB following 6 weeks of continuous culture. MDSCs produced from culture of CD34+ cells with GM-CSF/SCF for 6 weeks had the greatest suppressive function of T cell proliferation and had the highest expression of immunosuppressive molecules including iNOS, arginase 1 and IDO compared to those differentiated with G-CSF/SCF or M-CSF/SCF. MDSCs secreted IL-10, TGB-β, and VEGF. The infusion of expanded MDSCs significantly prolonged the survival and decreased the GVHD score in a NSG xenogeneic model of GVHD. Injected MDSCs increased IL-10 and TGF-β but decreased the level of TNF-α and IL-6 in the serum of treated mice. Notably, FoxP3 expressing regulatory T (Treg) cells were increased while IFN-γ (Th1) and IL-17 (Th17) producing T cells were decreased in the spleen of MDSC treated mice compared to untreated GVHD mice. Our results demonstrate that human MDSCs are generated from CB CD34+ cells using GM-CSF/SCF. These MDSCs exhibited potent immunosuppressive function, suggesting that they are useable as a treatment for inflammatory diseases such as GVHD

Comprehensive analysis of mycobacterium tuberculosis antigen-specific CD4+ T cell responses restricted by single HLA class II allotype in an individual

Mycobacterium tuberculosis infection is generally asymptomatic as latent tuberculosis, but it is still known as the world’s leading bacterial cause of death. The diagnosis of latent tuberculosis infection relies on the evidence of cellular immunity to mycobacterial antigens. Since the association between HLA class II and tuberculosis infection has been reported in several population groups, a detailed study on the CD4+ T cell response to major tuberculosis antigens is needed. To elucidate which HLA class II allotypes in an individual are preferentially used in tuberculosis, CD4+ T cells specific to TB10.4, Ag85b, ESAT-6, and CFP-10 of Mycobacterium tuberculosis antigens were analyzed comprehensively. A total of 33 healthy donors were analyzed by ex vivo and cultured ELISPOT using panels of artificial antigen-presenting cells expressing a single HLA class II allotype. The CD4+ T cell responses were increased by an average of 39-fold in cultured ELISPOT compared with ex vivo ELISPOT. In ex vivo and cultured ELISPOT, CD4+ T cell responses showed significantly higher by HLA-DR than those of HLA-DQ and HLA-DP locus. In cultured ELISPOT, 9 HLA-DR allotypes, 4 HLA-DQ allotypes, and 3 HLA-DP allotypes showed positive CD4+ T cell responses. Among ten donors with positive CD4+ T cell responses when tested for mixed Mycobacterium tuberculosis antigens, seven donors were positive for only a single allotype, and three were positive for two allotypes in an individual. However, only one allotype was used for a single antigen-specific response when a single tuberculosis antigen was used individually. These results on the distribution of HLA class II allotypes showing high CD4+ T-cell responses to Mycobacterium tuberculosis antigens and the intra-individual allotype dominance will provide valuable information for understanding the immunobiology and immunogenetics of tuberculosis, which can contribute to the development of more effective vaccines

Early prediction of molecular remission by monitoring BCR-ABL transcript levels in patients achieving a complete cytogenetic response after imatinib therapy for posttransplantation chronic myelogenous leukemia relapse

Imatinib induces a high complete cytogenetic response (CCR) rate in relapsed chronic myelogenous leukemia. By analyzing minimal residual disease (MRD) under the levels of CCR, we tried to assess the molecular response after imatinib therapy. By using real-time quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR), MRD was evaluated in 23 patients (3 in cytogenetic relapse, 6 in chronic phase, 9 in accelerated phase, and 5 in blast crisis) who were treated with standard-dose imatinib for relapsed chronic myelogenous leukemia after allogeneic stem cell transplantation. With a median therapy time of 399 days (range, 35–817 days), 19 (83%) patients achieved a CCR. Meanwhile, 11 (58%) of them achieved a molecular remission (MR), which was associated with improved survival. The Q-RT-PCR data were compared according to the best response (MR, n = 11; CCR, n = 8) in the patients achieving a CCR. The BCR-ABL/ABL ratios were similar in 2 groups at 3 months but were significantly different at 6 months (median, 0.0000012 for MR and 0.00022 for CCR; P = .003). The probability of a subsequent MR was significantly higher in patients with a lower BCR-ABL/ABL ratio at 6 months (100% for <0.0001 versus 33% for ≥0.0001; P = .006) or a greater reduction in the level between 3 and 6 months (log-reduction ≥1.0;, 100%; <1.0, 17%; P = .003). Q-RT-PCR is a reliable method for monitoring MRD: the early trends in the BCR-ABL/ABL ratio may be clinically useful in discriminating patients who will achieve an MR from those who will remain in CCR

Little Response of Cerebral Metastasis from Hepatocellular Carcinoma to Any Treatments

Objective : We retrospectively evaluated the survival outcome of patients with brain metastasis from hepatocellular carcinoma (HCC). Methods : Between 1991 and 2007, a total of 20 patients were diagnosed as having brain metastasis from HCC. The mean age of the patients was 55 +/- 13 years, and 17(85.0%) were men. Seventeen (85.0%) patients had already extracranial metastases. The median time from diagnosis of HCC to brain metastasis was 18.5 months. Fourteen (70.0%) patients had stroke-like presentation due to intracerebral hemorrhage (ICH). Ten (50.0%) patients had single or solitary brain metastasis. Among a total of 34 brain lesions, 31 (91.2%) lesions had the hemorrhagic components. Results : The median survival time was 8 weeks (95% Cl, 5.08-10.92), and the actuarial survival rates were 85.0%, 45.0%, 22.5%, and 8.4% at 4, 12, 24, and 54 weeks. Age < 60 years, treatment of the primary and/or extracranial lesions, and recurrent ICH were the possible prognostic factors (p = 0.044, p < 0.001, and p = 0.111, respectively). The median progression-free survival (PFS) time was 3 months (95% Cl, 0.95-5.05). Conclusion : The overall survival of the patients with brain metastasis from HCC was very poor with median survival time being only 8 weeks. However, the younger patients less than 60 years and/or no extracranial metastases seem to be a positive prognostic factor.Choi HJ, 2009, J NEURO-ONCOL, V91, P307, DOI 10.1007/s11060-008-9713-3Kim SR, 2006, WORLD J GASTROENTERO, V12, P6727Seinfeld J, 2006, J NEURO-ONCOL, V76, P93, DOI 10.1007/s11060-005-4175-3Cho DC, 2005, J CLIN NEUROSCI, V12, P699, DOI 10.1016/j.jocn.2004.08.026Chang L, 2004, SURG NEUROL, V62, P172, DOI 10.1016/j.surneu.2003.10.002Del Ben M, 2003, J EXP CLIN CANC RES, V22, P641El-Serag HB, 2002, J CLIN GASTROENTEROL, V35, pS72SALVATI M, 2002, J NEUROSURG SCI, V46, P77McIver JI, 2001, NEUROSURGERY, V49, P447Hayashi K, 2000, SURG NEUROL, V53, P379El-Serag HB, 1999, NEW ENGL J MED, V340, P745Peres MFP, 1998, ARQ NEURO-PSIQUIAT, V56, P658Deuffic S, 1998, LANCET, V351, P214Kim M, 1998, J NEURO-ONCOL, V36, P85TaylorRobinson SD, 1997, LANCET, V350, P1142Gaspar L, 1997, INT J RADIAT ONCOL, V37, P745LUCEY MR, 1997, LIVER TRANSPLANT SUR, V3, P628Murakami K, 1996, NEURORADIOLOGY, V38, pS31PATCHELL RA, 1990, NEW ENGL J MED, V322, P494OTSUKA S, 1987, NEUROL MED CHIR TOKY, V27, P654OKEN MM, 1982, AM J CLIN ONCOL-CANC, V5, P649PUGH RNH, 1973, BRIT J SURG, V60, P646

Clinical Application of 7.0 T Magnetic Resonance Images in Gamma Knife Radiosurgery for a Patient with Brain Metastases

In the study we assessed the distortion of 7.0 T magnetic resonance (MR) images in reference to 1.5 T MR images in the radiosurgery of metastatic brain tumors. Radiosurgery with Gamma Knife Perfexion® was performed for the treatment of a 54-yr-old female patient with multiple brain metastases by the co-registered images of the 7.0 T and 1.5 T magnetic resonance images (MRI). There was no significant discrepancy in the positions of anterior and posterior commissures as well as the locations of four metastatic brain tumors in the co-registered images between 7.0 T and 1.5 T MRI with better visualization of the anatomical details in 7.0 T MR images. This study demonstrates for the first time that 7.0 T MR images can be safely utilized in Perfexion® Gamma Knife radiosurgery for the treatment of metastatic brain tumors. Furthermore 7.0 T MR images provide better visualization of brain tumors without image distortion in comparison to 1.5 T MR images

HLA and Disease Associations in Koreans

The human leukocyte antigen (HLA), the major histocompatibility complex (MHC) in humans has been known to reside on chromosome 6 and encodes cell-surface antigen-presenting proteins and many other proteins related to immune system function. The HLA is highly polymorphic and the most genetically variable coding loci in humans. In addition to a critical role in transplantation medicine, HLA and disease associations have been widely studied across the populations world-wide and are found to be important in prediction of disease susceptibility, resistance and of evolutionary maintenance of genetic diversity. Because recently developed molecular based HLA typing has several advantages like improved specimen stability and increased resolution of HLA types, the association between HLA alleles and a given disease could be more accurately quantified. Here, in this review, we have collected HLA association data on some autoimmune diseases, infectious diseases, cancers, drug responsiveness and other diseases with unknown etiology in Koreans and attempt to summarize some remarkable HLA alleles related with specific diseases

Long-term follow-up of Fanconi anemia: clinical manifestation and treatment outcome

PurposeThe aim of this study was to characterize Korean patients with Fanconi anemia (FA), which is a rare but very challenging genetic disease.MethodsThe medical records of 12 FA patients diagnosed at Chonnam National University Hospital from 1991 to 2012 were retrospectively reviewed.ResultsThe median age at diagnosis was 6.2 years. All patients showed evidence of marrow failure and one or more physical stigmata. Chromosome breakage tests were positive in 9 out of 11 available patients. The median follow-up duration was 69.5 months. The Kaplan-Meier (KM) survival of all patients was 83.3% at 10 years and 34.7% at 20 years, respectively. Seven patients underwent 9 stem cell transplantations (SCTs). Among them, 5 were alive by the end of the study. Ten-year KM survival after SCT was 71.4% with a median follow-up of 3.4 years. All 5 patients treated with supportive treatment alone died of infection or progression at the median age of 13.5 years, except for one with short follow-up duration. Acute leukemia developed in 2 patients at 15.4 and 18.1 years of age. Among 6 patients who are still alive, 3 had short stature and 1 developed insulin-dependent diabetes mellitus.ConclusionWe provide information on the long-term outcomes of FA patients in Korea. A nation-wide FA registry that includes information of the genotypes of Korean patients is required to further characterize ethnic differences and provide the best standard of care for FA patients

Recurrent Juvenile Nasopharyngeal Angiofibroma Treated with Gamma Knife Surgery

Radiosurgery has been rarely applied for juvenile nasopharyngeal angiofibroma (JNA) and cumulative reports are lacking. The authors report a case of successful treatment of recurred JNA with gamma knife surgery (GKS). A 48-yr-old man was presented with right visual acuity deterioration and brain magnetic resonance images (MRI) disclosed a 3 cm-sized intraorbital mass in the right orbit. He underwent a right fronto-temporal craniotomy and the mass was subtotally removed to preserve visual function. Histological diagnosis confirmed JNA in typical nature. However, the vision gradually worsened to fail four years after operation. MRI then showed regrowth of the tumor occupying most of the right orbit. GKS was done for the recurred lesion. A dose of 17 Gy was delivered to the 50% isodose line of tumor margin. During the following four-year follow-up period, the mass disappeared almost completely without any complications. Usually JNA can be exclusively diagnosed by radiological study alone. So this report of successful treatment of JNA with GKS may provide an important clue for the novel indication of GKS