BACKGROUND: The interaction between killer immunoglobulin-like receptors (KIRs) and HLA class I regulates natural killer (NK) cell cytotoxicity and function. The impact of NK cell alloreactivity through KIR in liver transplantation remains unelucidated. Since the frequency of HLA-C and KIR genotypes show ethnic differences, we assessed the impact of HLA-C, KIR genotype, or KIR-ligand mismatch on the allograft outcome of Korean liver allografts. METHODS: One hundred eighty-two living donor liver transplant patients were studied. Thirty-five patients (19.2%) had biopsy-confirmed acute rejection (AR), and eighteen (9.9%) had graft failure. The HLA-C compatibility, KIR genotypes, ligand-ligand, and KIR-ligand matching was retrospectively investigated for association with allograft outcomes. RESULTS: Homozygous C1 ligands were predominant in both patients and donors, and frequency of the HLA-C2 allele in Koreans was lower than that in other ethnic groups. Despite the significantly lower frequency of the HLA-C2 genotype in Koreans, donors with at least one HLA-C2 allele showed higher rates of AR than donors with no HLA-C2 alleles (29.2% vs 15.7%, P=0.0423). Although KIR genotypes also showed ethnic differences, KIR genotypes and the number of activating KIR/inhibitory KIR were not associated with the allograft outcome. KIR-ligand mismatch was expected in 31.6% of Korean liver transplants and had no impact on AR or graft survival. CONCLUSIONS: This study could not confirm the clinical impact of KIR genotypes and KIR-ligand mismatch. However, we demonstrated that the presence of HLA-C2 allele in the donor influenced AR of Korean liver allografts.
Adult ; Alleles ; Asian Continental Ancestry Group/*genetics ; Female ; Genotype ; Graft Rejection ; Graft Survival ; HLA-C Antigens/*genetics ; Homozygote ; Humans ; Killer Cells, Natural/cytology/immunology ; Ligands ; *Liver Transplantation ; Male ; Middle Aged ; Proportional Hazards Models ; Receptors, KIR/chemistry/*genetics/metabolism ; Republic of Korea ; Tissue Donors ; Transplantation, Homologous

OBJECTIVETo investigate the effectiveness and safety of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) in ultra high risk chronic lymphocytic leukemia (CLL) patients with the deletion of p53 to deepen the understanding of allo-HSCT in the treatment of CLL.

METHODSIn this retrospective study, a total of 4 ultra high risk CLL patients with the deletion of p53 in our center between July 2012 and Jan 2014 were enrolled. The RIC regimen was administered and the hematopoietic reconstitution, transplantation related mortality (TRM), overall survival (OS), progress free survival (PFS) were evaluated.

RESULTSWe registered 4 patients with the median age of 56 years (49-61 years), including 3 males and 1 female. The median mononuclear cells (MNC) and CD34(+) cells were 6.54 (2.85-14.7) × 10(8)/kg (recipient body weight) and 5.81 (2.85-7.79) × 10(6)/kg (recipient body weight), respectively. The median time of the neutrophil recovery was 11 days (range of 9-12 days), and the median time of the platelet recovery 5.5 days (range of 0-11 days). Three patients (75%) attained a full donor chimerism at day 28 after transplantation and one (25%) got a mixed chimerism of donor and recipient. During the follow-up at a median time of 26.5 months (range of 21-39 months), 2 (50%) patients developed acute graft versus host disease (aGVHD) grade I and 2 (50%) patients got CMV infection. One patient got herpes zoster virus and EB virus infections. No transplantation related mortality was found in the 4 patients. One patient who was in partial response status progressed 5 months after transplantation, and the other 3 patients remained in durable remission after allo-HSCT.

CONCLUSIONThese results suggested that RIC allo-HSCT showed durable remission, good tolerance and acceptable toxicity, which could be a better option for the treatment of ultra high risk CLL patients with the deletion of p53 and was worth to be investigated and applied widely in future.

Disease-Free Survival ; Female ; Gene Deletion ; Genes, p53 ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; genetics ; therapy ; Male ; Middle Aged ; Retrospective Studies ; Transplantation Conditioning ; Treatment Outcome ; Tumor Suppressor Protein p53 ; genetics

OBJECTIVETo analyze the effect of sorafenib as salvage therapy used before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in refractory relapsed FLT3-positive acute myeloid leukemia (AML).

METHODSA total of 16 patients with refractory relapsed FLT3-positive AML, including 10 refractory relapsed pre-transplantation and 6 relapsed after allo-HSCT, were enrolled in this retrospective study. Sorafenib treatment protocols included sorafenib in combination with chemotherapy inducing remission, and sorafenib monotherapy as mauntenance treatment after complete remission (CR).

RESULTSThirteen of the 16 patients achieved CR after one or two courses of induction therapy, including 7 refractory relapsed pre-transplantation and 6 relapsed after allo-HSCT. With a median follow up of 472 (range, 59-1569) days post-transplantation, 12 patients survived and 4 died. Causes of death included leukemia relapse (n=3) and acute graft-versus-host disease (n=1). The 2-year overall and disease-free survival post-transplantation of the 16 patients were (75.0±10.8) % and (50.5±13.7) % respectively. The main side effect of sorafenib was the skin rash. The incidence of rash was lower in the patients used sorafenib pre-transplantation than those post-transplantation (30.0% vs 75.0%, P=0.043).

CONCLUSIONSorafenib used as salvage therapy befor and/or after transplantation for refractory relapsed FLT3-positive AML could reduce the relapse rate and improve the survival.

Antineoplastic Agents ; therapeutic use ; Disease-Free Survival ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Induction Chemotherapy ; Leukemia, Myeloid, Acute ; genetics ; therapy ; Mutation ; Niacinamide ; analogs & derivatives ; therapeutic use ; Phenylurea Compounds ; therapeutic use ; Recurrence ; Remission Induction ; Retrospective Studies ; Salvage Therapy ; Treatment Outcome ; fms-Like Tyrosine Kinase 3 ; genetics

BACKGROUND/AIMS: The relationship between patient survival and biopsy-proven acute rejection (BPAR) in liver transplant recipients with hepatitis C remains unclear. The aims of this study were to compare the characteristics of patients with and without BPAR and to identify risk factors for BPAR. METHODS: We retrospectively reviewed the records of 169 HCV-RNA-positive patients who underwent LT at three centers. RESULTS: BPAR occurred in 39 (23.1%) of the HCV-RNA-positive recipients after LT. The 1-, 3-, and 5-year survival rates were 92.1%, 90.3%, and 88.5%, respectively, in patients without BPAR, and 75.7%, 63.4%, and 58.9% in patients with BPAR (P<0.001). Multivariate analyses showed that BPAR was associated with the non-use of basiliximab and tacrolimus and the use of cyclosporin in LT recipients with HCV RNA-positive. CONCLUSION: The results of the present study suggest that the immunosuppression status of HCV-RNA-positive LT recipients should be carefully determined in order to prevent BPAR and to improve patient survival.
Antibodies, Monoclonal/therapeutic use ; Biopsy ; Cyclosporine/therapeutic use ; Drug Therapy, Combination ; Genotype ; Graft Rejection/mortality/*prevention & control ; Hepacivirus/genetics/isolation & purification ; Hepatitis C/drug therapy/*virology ; Humans ; Immunosuppressive Agents/*therapeutic use ; *Liver Transplantation/adverse effects ; Polymerase Chain Reaction ; RNA, Viral/blood ; Recombinant Fusion Proteins/therapeutic use ; Recurrence ; Retrospective Studies ; Survival Rate ; Tacrolimus/therapeutic use

OBJECTIVETo analyze the treatment outcome of a consecutive series of 100 leukemia patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT).

METHODSThe clinical data of leukemia patients received allo-HSCT were analyzed retrospectively, the therapeutic efficacy was summarized. 100 evaluable cases of leukemia included 47 cases of AML, 33 cases of ALL, 2 cases of AL (biphenotypic), 16 CML and 2 CMML. Before transplantation, 76 cases were in first complete remission, 9 cases in second or greater complete remission and 15 cases in non-remission or relapse. All the patients received peripheral blood hematopoietic stem cell transplantation (PBHSCT). The conditioning regimen of human leukocyte antigen (HLA)-matched allo-HSCT group was modified BuCy, but in HLA-mismatched group Fludarabine and anti-human thymocyte globulin (ATG) was added. CsA+MTX regimen was used for prophylaxis of graft-versus-host disease (GVHD) in HLA-identical allo-HSCT, while additional MMF was added in HLA-mismatched group. The average time of follow-up was 13 months.

RESULTSAt the last follow-up, 66.0% (66/100) patients survived, 53.0% (53/100) patients survived without leukemia, 28.0% (28/100) patients relapsed and 34.0% (34/100) patients died, 44.1% patients of them died from infectious pulmonary complications. During transplantation, 65.0% of the patients were suffered from lung infection. The overall survival (OS) and disease-free survival (DFS) of all cases was 60.9% and 48.8%, respectively. The recurrence rate was significantly higher in non-remission (66.7%) than in CR (21.2%) patients (P < 0.05). The cumulative incidence of GVHD in HLA-mismatched transplantation was 60.8%, which was significantly higher than that of HLA-matched transplantation (38.8%) (P < 0.05).

CONCLUSIONAllo-HSCT can cure a significant proportion of leukemia patients, especially for those in CR status. Since the incidence of infectious pulmonary complications after allo-HSCT is still high, much more attention should be paid to it. The comprehensive prognosis of HLA-matched transplantation is better than the HLA-mis-matched transplantation.

Antilymphocyte Serum ; therapeutic use ; Disease-Free Survival ; Graft vs Host Disease ; prevention & control ; HLA Antigens ; genetics ; Humans ; Incidence ; Leukemia ; therapy ; Peripheral Blood Stem Cell Transplantation ; Recurrence ; Retrospective Studies ; Transplantation Conditioning ; Treatment Outcome ; Vidarabine ; analogs & derivatives ; therapeutic use

OBJECTIVETo establish a calculated panel reactive antibody (CPRA) method to analyze the donor-recipient incompatibility rate in PRA-positive kidney recipients and estimate the probability of these recipients to receive kidney transplantation.

METHODSBased on the database of HLA-A, -B, -DR genes and A-B, A-DR, B-DR, A-B-DR haplotype frequencies collected from 2004 donors from Jan 2000 to Dec 2012, we analyzed CPRA in 202 PRA-positive recipients and evaluated the consistency between PRA and CPRA assessments using a CPRA-Java calculator software, which returned a percentage of CPRA (representing the probability of unacceptable HLA in the donor group) after input of HLA-specific antibodies of a PRA-positive recipient.

RESULTSThe mean PRA intensity of the 202 PRA-positive recipients was (23.12∓17.83)% with a mean CPRA% of (46.07∓23.30)%. A significant difference was found between the mean PRA% and CPRA% in low sensitized recipients (PRA 0-10%) [(6.87∓2.41)% vs (21.63∓11.75)%, P<0.05) and in moderately sensitized recipients (PRA 10%-30%) [(20.15∓5.70)% vs (50.56∓16.86)%, P<0.05), but not in highly sensitized recipients (PRA>30%); The concordance rates between PRA% and CPRA% in the 3 groups were 19.35% (P<0.05), 10.99% (P<0.05), and 100% (P>0.05), respectively.

CONCLUSIONSLowly sensitized kidney recipients might have a lower probability of actually receiving a transplant than PRA% shows. A PRA%>30% is a risk factor for kidney transplantation. PRA reflects the sensitized level of a renal recipient, and reliable detection of HLA antibody specificity is of critical importance. CPRA accurately reflects the probability of a recipient to receive a transplant to assist clinicians in predicting the waiting time and selecting the transplant approach.

Antibodies ; Antibody Specificity ; Graft Rejection ; immunology ; Graft Survival ; immunology ; HLA Antigens ; genetics ; Haploidy ; Histocompatibility Testing ; methods ; Humans ; Kidney Transplantation

Hepatocyte growth factor (HGF) is a potent angiogenic factor that can stimulate the production of blood vessels in ischemic tissue. We investigated whether gene therapy using HGF-expressing adenovirus could enhance skin flap survival. Sprague-Dawley rats were randomly divided into three groups. Rats were subdermally injected with HGF-expressing adenovirus (HGF virus group), recombinant HGF (rhHGF group), or phosphate buffered saline (PBS group) 2 days before and immediately after 3 x 9 cm caudal flap elevation. The survival area of the skin flap, the ratio of blood flow, CD31-positive vessels and, VEGF expression were examined. Skin flap viability was significantly increased in the HGF virus group compared to the rhHGF and PBS groups (71.4% +/- 5.9%, 63.8%+/- 6.4%, and 39.2% +/- 13.0%, respectively) (P = 0.025). Furthermore, the blood flow ratio was significantly increased in the HGF virus group. In the HGF virus group, the number of CD31-positive vessels and vascular endothelial growth factor (VEGF) expression were significantly increased. Gene therapy using HGF-expressing adenovirus increase VEGF expression, the number of viable capillaries, and blood flow to the flap, thereby improving skin flap survival.
Adenoviridae/genetics ; Animals ; Genetic Therapy/*methods ; Graft Survival/genetics ; Hepatocyte Growth Factor/biosynthesis/*genetics ; Male ; Models, Animal ; Neovascularization, Physiologic/*genetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Reconstructive Surgical Procedures ; Skin Transplantation/*methods ; Surgical Flaps/*surgery

OBJECTIVETo explore the impact of interleukin-18 (IL-18) single nucleotide polymorphisms on outcomes of hematologic malignancies with HLA-matched sibling donor hematopoietic stem cell transplantation (allo-HSCT).

METHODSSingle- nucleotide polymorphisms in IL-18 promoter was detected by PCR-sequence-specific primer analysis (PCR-SSP) in 93 recipients and their HLA matched sibling donors. Hematopoietic reconstitution, incidences of graft versus host disease (GVHD) and infections, transplant related mortality (TRM), and disease free survival (DFS) were analyzed.

RESULTSIn comparison with -137 G/C+C/C donor genotype, patients with -137 G/G donor genotype had shorter duration of neutrophil recovery [15(11-23) days vs 17(11-24) days, P=0.01], higher incidence of extensive chronic GVHD (20.6% vs 3.3%, P=0.029), but no difference in the interval of platelet recovery [20(11-46) days vs 20(7-38) days, P=0.844]. The incidence of extensive chronic GVHD in -607 C/C donor genotype (31.6%) was significantly higher than that (10.8%) in C/A + A/A donor genotype (P=0.024). Recipients with -607 C/C genotype also had higher incidence (33.3%) of extensive chronic GVHD than those with C/A+A/A genotype (10.7%, P=0.016). There were no differences in acute GVHD, TRM, and DFS between different genotypes.

CONCLUSIONIL-18 -137 G homozygous genotype in donor facilitated neutrophil reconstitution, but increased the risk of extensive chronic GVHD in patients with allo-HSCT.

Adolescent ; Adult ; Child ; Child, Preschool ; Disease-Free Survival ; Female ; Genotype ; Graft vs Host Disease ; epidemiology ; Hematologic Neoplasms ; genetics ; therapy ; Hematopoietic Stem Cell Transplantation ; adverse effects ; methods ; Humans ; Incidence ; Interleukin-18 ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Siblings ; Tissue Donors ; Transplantation, Homologous ; Young Adult

OBJECTIVETo evaluate the influence of major histocompatibility complex class I chain-related gene A (MICA) antibodies on acute rejection (AR) and renal function in early stage after renal transplantation.

METHODSA total of 197 renal transplant candidates admitted in Nanfang Hospital in 2009-2010 were enrolled in this study. MICA antibodies and their specificity were detected in all the patients, and 139 patients were followed up for early acute rejection (AR) and graft function after transplantation.

RESULTSMICA antibodies were positive before transplantation in 45 candidates (22.84%). Eleven specific MICA antibodies were identified, among which the frequency of MICA019 antibody (65.7%) was significantly higher than that of MICA015 (8.6%) and MICA017 (8.6%) (P<0.01). Eighteen patients with positive MICA antibodies were single-specific and 17 were polyspecific (51.4% vs 48.6% ). Of the 139 patients undergoing renal transplantation, 39 developed early AR (28.1%). Of the 45 candidates positive for MICA antibodies, 38 received renal transplantation and early AR occurred in 14 of them (36.8%); 101 of 152 candidates negative for MICA antibodies underwent renal transplantation, and 25 experienced early AR (24.8%).

CONCLUSIONMICA019 antibody is a frequent MICA antibody possibly due to the high frequency MICA019 gene in Chinese population.

Adult ; Antibodies ; immunology ; Antibody Specificity ; Female ; Graft Rejection ; immunology ; Graft Survival ; immunology ; Histocompatibility Antigens Class I ; genetics ; immunology ; Humans ; Kidney Transplantation ; Male ; Middle Aged

OBJECTIVETo investigate the effect of inhibitory and activating KIRs on a cohort of Chinese leukemia patients who received haplo-identical hematopoietic stem cell transplantation (HSCT).

METHODSDonor's inhibitory and activating KIRs and recipient's HLA-C from 47 cases who received haplo-identical HSCT were tested by PCR-SSP. 2 year overall survival (OS), incidence of severe (grade III to IV) acute GVHD (aGVHD) and relapse rate (RR) were analyzed.

RESULTS(1) According to Matched (M) vs Mis-Matched (MM) between donor's inhibitory KIR and recipient's HLA-C1/C2 subgroup, 2 year OS rate in M group [(87.5 +/- 8.3)%] was significantly higher than that in MM group (54.5 +/- 9.0)%, (P = 0.03). Lower incidence of relapse rate was seen in M group than in M/MM groups [0 vs (25.4 +/- 9.5)%, P = 0.05]. In 30 cases of myeloid leukemia patients, there was lower RR in M group than in MM groups [0 vs (35.0 +/- 14.4)%, P = 0.04]. (2) According to the 3 activating KIR genes: KIR2DS1/ KIR2DS2/ KIR2DS3, lower incidence of grade III-IV aGVHD was seen in KIR2DS1 (+) group than in KIR2DS1 (-) group (13% vs 28%, respectively, P > 0.05); and so was done in KIR2DS3 (+) group (11% vs 26%, respectively, P > 0.05). The RR was lower in KIR2DS2 (+) group [0% vs (17.3 +/- 7.1)%, respectively, P > 0.05].

CONCLUSIONSIn our haplo-identical HSCT setting, match between donor's inhibitory KIR and recipient's HLA-C can significantly reduce the incidence of relapse rate and improve OS. Although lower incidences of severe aGVHD are noted in the donors with KIR2DS1 (+) or KIR2DS3 (+), and lower relapse rate is noted in the donors with KIR2DS2 (+) but without statistic difference, no remarkable effects of activating KIRs on OS have been found in our relatively small clinical series.

Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Genotype ; Graft vs Host Disease ; HLA-C Antigens ; genetics ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Male ; Middle Aged ; Receptors, KIR ; classification ; Recurrence ; Siblings ; Survival Rate ; Tissue Donors ; Transplantation, Homologous ; Young Adult