Biomarkers in chronic graft-versus-host disease: quo vadis?

Biomarkers are increasingly used for diagnosis and treatment of transplant-related complications including the first biomarker-driven interventional trials of acute graft-versus-host disease (GvHD). In contrast, the development of biomarkers of chronic GvHD (cGvHD) has lagged behind due to a broader variety of manifestations, overlap with acute GvHD, a greater variation in time to onset and maximum severity, and lack of sufficient patient numbers within prospective trials. An international workshop organized by a North-American and European consortium was held in Marseille in March 2017 with the goal to discuss strategies for future biomarker development to guide cGvHD therapy. As a result of this meeting, two areas were prioritized: the development of prognostic biomarkers for subsequent onset of moderate/severe cGvHD, and in parallel, the development of qualified clinical-grade assays for biomarker quantification. The most promising prognostic serum biomarkers are CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, and CD163. Urine-proteomics and cellular subsets (CD4+ T-cell subsets, NK cell subsets, and CD19+CD21low B cells) represent additional potential prognostic biomarkers of cGvHD. A joint effort is required to verify the results of numerous exploratory trials before any of the potential candidates is ready for validation and subsequent clinical application.

Proteomic Characterization Reveals That MMP-3 Correlates With Bronchiolitis Obliterans Syndrome Following Allogeneic Hematopoietic Cell and Lung Transplantation.

Improved diagnostic methods are needed for bronchiolitis obliterans syndrome (BOS), a serious complication after allogeneic hematopoietic cell transplantation (HCT) and lung transplantation. For protein candidate discovery, we compared plasma pools from HCT transplantation recipients with BOS at onset (n = 12), pulmonary infection (n = 16), chronic graft-versus-host disease without pulmonary involvement (n = 15) and no chronic complications after HCT (n = 15). Pools were labeled with different tags (isobaric tags for relative and absolute quantification), and two software tools identified differentially expressed proteins (≥1.5-fold change). Candidate proteins were further selected using a six-step computational biology approach. The diagnostic value of the lead candidate, matrix metalloproteinase 3 (MMP3), was evaluated by enzyme-linked immunosorbent assay in plasma of a verification cohort (n = 112) with and without BOS following HCT (n = 76) or lung transplantation (n = 36). MMP3 plasma concentrations differed significantly between patients with and without BOS (area under the receiver operating characteristic curve 0.77). Consequently, MMP3 represents a potential noninvasive blood test for diagnosis of BOS.

Somatic mutations in the HLA genes of patients with hematological malignancy.

Somatic mutations and genomic alterations are frequent events in the clonal evolution of hematologic malignancies. Recent studies have reported copy neutral loss of heterozygosity (LOH) for the mismatched human leukocyte antigen (HLA) haplotype in patients relapsed after haploidentical hematopoietic cell transplantation (HCT) for a hematologic malignancy. Herein, we report 15 cases of somatic mutations in the HLA genes of patients with a variety of hematologic diseases, including acute myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma, encountered at our institute over the past decade. While two of the cases were identified in patient relapse specimens collected post-HCT, 13 cases were found in peripheral blood specimens submitted for HLA typing prior to transplantation. Ten patients exhibited acquired LOH for all or part of one HLA haplotype. Five other cases involved somatic mutations in the nucleotide sequences of common HLA-A or HLA-B alleles. Since they are not systematically evaluated prior to HCT, acquired mutations in HLA genes are likely under reported. Beyond the implications for accurate HLA typing and donor selection, alternations that result in the loss of HLA expression may allow escape from immune surveillance and adversely impact transplant outcome.

Effects of chronic exposure of diets with reduced concentrations of aflatoxin and deoxynivalenol on growth and immune status of pigs.

This study investigated the growth and immune responses of pigs fed diets containing reduced concentrations of aflatoxin (AF) and deoxynivalenol (DON) from naturally contaminated corn. Sixty gilts (13.9 ± 0.2 kg of BW) were randomly assigned to 4 treatments (5 replicate pens per treatment and 3 pigs per pen): A (a control diet without detectable AF and DON); B (a diet with 60 µg of AF/kg and 300 µg of DON/kg); C (a diet with 120 µg of AF/kg and 600 µg of DON/kg); and D (a diet with 180 µg of AF/kg and 900 µg of DON/kg). Pigs were allowed ad libitum access to feed and water for 33 d. Feed intake and BW were measured weekly and pigs were bled (8 mL) on d 33 to measure the numbers of blood cells, to conduct liver function tests, and to measure immunological variables including IgG, IgM, interferon γ, IL4, IL6, and tumor necrosis factor α. One pig representing the average BW of each pen was killed to obtain the liver, kidneys, and spleen for weight, tissue color measurement, and histological evaluation of tissue damage. When compared with A, pigs in C and D tended to have reduced ADG (0.52 vs. 0.43 and 0.41 kg/d, respectively; P = 0.058) and ADFI (1.04 vs. 0.92 and 0.88 kg/d, respectively; P = 0.061). White blood cell count of pigs in D (23.4 × 10(3) cells/µL) was greater (P < 0.05) than those in A, B, and C (18.4, 18.5, and 16.8 × 10(3) cells/µL, respectively. Serum tumor necrosis factor α concentration of pigs in D (335 pg/mL) differed (P < 0.05) from those in A and C (299 and 290 pg/mL, respectively). Pigs in B and D had greater (P < 0.05) fibrosis in liver tissues than those in A. Collectively, this study shows that diets containing both AF and DON greater than 60 and 300 µg/kg, respectively, may reduce growth and decrease feed intake, whereas diets containing 120 µg of AF/kg and 600 µg of DON/kg may result in altered immune health, systemic inflammation, and partial liver damage, causing further reduction in growth of pigs.

Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission.

Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients does not have such a donor and will require an alternative donor if HCT is to be undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; 9/10, n=29) or MRD (n=135) HCT from 1996 to 2007. The 5-year estimates of overall survival, relapse and nonrelapse mortality (NRM) were 57.9, 29.7 and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any end point. The adjusted hazard ratios (HRs) were 1.43 (0.89-2.30, P=0.14) for overall mortality, 1.17 (0.66-2.08, P=0.60) for relapse and 1.79 (0.86-3.74, P=0.12) for NRM, respectively, and the adjusted odds ratio for grades 2-4 acute graft-versus-host disease was 1.50 (0.70-3.24, P=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR 1.16 (0.52-2.61), P=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.

Early risk factors for nonadherence in pediatric type 1 diabetes: a review of the recent literature.

Nonadherence to different aspects of the diabetes regimen is common. Problems early in the course of illness predict later difficulties with nonadherence; conversely, good management early on protects against later complications. Screening for early risk factors at the time of diabetes diagnosis is therefore critical for promoting the health of children with type 1 diabetes. The purpose of this paper is to review and synthesize the recent empirical literature on early risk factors for nonadherence in type 1 diabetes, with a focus on three specific adherence behaviors: insulin administration, blood glucose monitoring, and clinic attendance. Risk factors are considered within several broad categories: sociodemographic barriers that limit access to care; child and parent factors that affect adherence both directly and indirectly via their impact on the development of family teamwork; and family interactions with their health-care providers. We integrate the different findings into a "simple model" that can be used to develop efficient screening protocols that can in turn guide efforts at preventive intervention.

Energy production, nutrient recovery and greenhouse gas emission potentials from integrated pig manure management systems.

Improper management of pig manure has resulted in environmental problems such as surface water eutrophication, ground water pollution, and greenhouse gas emissions. This study develops and compares 14 alternative manure management scenarios aiming at energy and nutrient extraction. The scenarios based on combinations of thermal pretreatment, anaerobic digestion, anaerobic co-digestion, liquid/solid separation, drying, incineration, and thermal gasification were compared with respect to their energy, nutrient and greenhouse gas balances. Both sole pig manure and pig manure mixed with other types of waste materials were considered. Data for the analyses were obtained from existing waste treatment facilities, experimental plants, laboratory measurements and literature. The assessment reveals that incineration combined with liquid/solid separation and drying of the solids is a promising management option yielding a high potential energy utilization rate and greenhouse gas savings. If maximum electricity production is desired, anaerobic digestion is advantageous as the biogas can be converted to electricity at high efficiency in a gas engine while allowing production of heat for operation of the digestion process. In conclusion, this study shows that the choice of technology has a strong influence on energy, nutrient and greenhouse gas balances. Thus, to get the most reliable results, it is important to consider the most representative (and up-to-date) technology combined with data representing the area or region in question.

Incidence of humoral sensitization in HLA partially mismatched hematopoietic stem cell transplantation.

As part of the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), seven centers participated in a collaborative project to determine whether any significant humoral sensitization occurred post-transplant among recipients of HLA partially mismatched hematopoietic cell transplants (HCTs). A total of 140 donor/recipient pairs were enrolled with a total of 367 pre-and post-transplant sera analyzed. The majority of the samples (69.1%) were obtained within 30-90 days post-HCT. HLA-specific antibodies were defined using single antigen bead assays on a Luminex platform with a positive cutoff value of 1000 normalized median fluorescence intensity (MFI). There was an overall incidence of post-HCT sensitization toward donor HLA mismatches of 5.7%; however, all cases were among recipients of one HLA haplotype-mismatched grafts under nonmyeloablative, pre-transplant conditioning. Among the one haplotype-mismatched recipients, 15.7% (8/51) developed donor HLA-specific antibodies and 29.4% also had antibodies directed toward third party HLA antigens. Among the donor-specific antibodies, 9.8% were directed toward HLA class I antigens; 7.8% were against class II antigens; and 2.0% had both class I and II specificity. The relative strength of post-transplant antibodies was low with no significant difference in the mean maximum MFI values between third party and donor-specific antibodies. Because only a small number (10.2%) of the post-transplant samples were obtained 180 days or more post-HCT, longer term study is needed to evaluate any clinical relevance of these low-to-moderate levels of donor-specific antibody in one haplotype-mismatched recipients, as well as to determine whether any other antibodies occur at later times.

Resequencing of the human major histocompatibility complex in patients with rheumatoid arthritis and healthy controls in Alaska Natives of Southeast Alaska.

High prevalence and severity of rheumatoid arthritis (RA) with an early age of onset have previously been described in Alaska Native and American Indian (AN/AI) populations. The contribution of HLA-DRB1 alleles encoding a similar amino acid sequence, referred to as the shared epitope (SE), to RA risk is well recognized in multiple populations worldwide. DRB1*1402 allele is the major SE-encoding allele in AN/AI populations. However, DRB1*1402 is highly prevalent in healthy Alaska Natives of Southeast Alaska (AN), with no significant difference from RA patients, indicating this allele alone is not informative for defining genetic risk and non-human leukocyte antigen (non-HLA) genes are likely important in AN. We sought to deep resequence the human major histocompatibility complex (MHC) to characterize the single-nucleotide polymorphism (SNP) haplotypes within this region in RA cases and controls in AN. Approximately 99 kb of the MHC was resequenced with 95 amplicons throughout this region. Thirty-four cases and 74 controls were examined. A total of 696 SNPs were discovered from 85 of the selected 95 amplicons. Disease association signals were detected for nine of the 95 amplicons analyzed. Increased risk of RA was associated with five amplicons in the class I, class II or class III region and resistance to disease with four amplicons in the class I region. Our results indicate that non-HLA MHC genes and/or unknown exogenous factors likely modulate risk of RA in the AN population.

Correlation of interleukin-10 gene haplotype with hepatocellular carcinoma in Taiwan.

Polymorphisms in cytokine genes can influence immune responses, inflammation and tissue injury, and may affect the outcome of hepatitis B virus (HBV) infection. We analyzed single nucleotide polymorphisms (SNP) in the interleukin (IL)-10 gene among 344 HBV carriers and 208 patients with hepatocellular carcinoma (HCC). Genotypes and haplotypes were tested for association with HCC. IL-10/-592 C/C genotype was associated with a higher risk for HCC compared with IL-10/-592 A/C and A/A genotypes [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.2-3.6]. IL-10/1927 A/A genotype was also associated with a higher risk for HCC compared with IL-10/1927 A/C and C/C genotypes (OR: 1.5, 95% CI: 1.0-2.2). Haplotype analysis revealed that the homozygosity of the C-A haplotype (defined by SNPs at positions -592 and 1927) of IL-10 gene conveys the highest risk for HCC among HBV carriers compared with the homozygosity for the A-C haplotype (OR: 2.6, 95% CI: 1.3-4.9). The results demonstrate that IL-10 gene polymorphism can affect the outcome of chronic HBV infection. Further studies are necessary to clarify how variation in the IL-10 gene affects IL-10 function and risk of HCC.

D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus.

AIMS/HYPOTHESIS: The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk. METHODS: We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden. RESULTS: We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15-=0.017 (95% CI 0.005, 0.062), p<0.001]. CONCLUSIONS/INTERPRETATION: Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk.

Regulation of pancreatic beta-cell mass and proliferation by SOCS-3.

Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Suppressors of cytokine signaling (SOCS) proteins are specific inhibitors of the JAK/STAT pathway acting through a negative-feedback loop. To investigate in vivo effects of SOCS-3 in growth hormone (GH)/prolactin signaling in beta-cells we generated transgenic mice with beta-cell-specific overexpression of SOCS-3. The relative beta-cell proliferation and volume in the mice were measured by morphometry. Beta-cell volume of transgenic female mice was reduced by over 30% compared with beta-cell volume in wild-type female mice. Stimulation of transgenic islets in vitro with GH showed a reduced tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH- but not GLP-1-mediated islet cell proliferation, indicating that the decreased beta-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced beta-cell proliferation by SOCS-3. In spite of the reduced beta-cell volume the transgenic female mice exhibited enhanced glucose tolerance compared with wild-type littermates following an oral glucose-tolerance test. Together these data suggest that SOCS-3 modulates cytokine signaling in pancreatic beta-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.

Mechanism of protein tyrosine phosphatase 1B-mediated inhibition of leptin signalling.

Upon leptin binding, the leptin receptor is activated, leading to stimulation of the JAK/STAT signal transduction cascade. The transient character of the tyrosine phosphorylation of JAK2 and STAT3 suggests the involvement of protein tyrosine phosphatases (PTPs) as negative regulators of this signalling pathway. Specifically, recent evidence has suggested that PTP1B might be a key regulator of leptin signalling, based on the resistance to diet-induced obesity and increased leptin signalling observed in PTP1B-deficient mice. The present study was undertaken to investigate the mechanism by which PTP1B mediates the cessation of the leptin signal transduction. Leptin-induced activation of a STAT3 responsive reporter was dose-dependently inhibited by co-transfection with PTP1B. No inhibition was observed when a catalytically inactive mutant of PTP1B was used or when other PTPs were co-transfected. PTP1B was able to dephosphorylate activated JAK2 and STAT3 in vitro, whereas either no or a minimal effect was observed with cluster of differentiation 45 (CD45), PTPalpha and leukocyte antigen-related (LAR). By utilisation of a selective PTP1B inhibitor, the leptin-induced STAT3 activation was enhanced in cells. In conclusion, these results suggested that the negative regulatory role of PTP1B on leptin signalling is mediated through a direct and selective dephosphorylation of the two signalling molecules, JAK2 and STAT3.

HLA-Cw*0409N is associated with HLA-A*2301 and HLA-B*4403-carrying haplotypes.

The associations of HLA-B*4402 and HLA-B*4403 with alleles of HLA-A and HLA-Cw were investigated in panels of HLA-B*4403 and HLA-B*4402 homozygous individuals and in selected individuals carrying HLA-Cw*04 and HLA-B*4403. Some of these individuals were genotyped and also carried (HLA-DRB1*0701, DQB1*02). Among the latter, we studied individuals carrying the conserved extended haplotype (CEH) [HLA-Cw*04, B*4403, FC31, DRB1*0701, DQB1*02]. Four different common (HLA-Cw*, B*44) haplotypes were identified that extended to the HLA-A locus: HLA-A*0201, Cw*0501, B*4402; HLA-A*2902, Cw*1601, B*4403; HLA-A*2301, Cw*0401, B*4403; and HLA-A*2301, Cw*0409N, B*4403. We identified eight unrelated examples of the allele HLA-Cw*0409N. HLA-A*2301 was associated with both HLA-Cw*0401 and HLA-Cw*0409N, suggesting that HLA-Cw*0409N may have arisen from a mutation in a CEH. We estimate that approximately 2 to 5 in 1000 Caucasian individuals carry the allele HLA-Cw*0409N, making it one of the most frequent null HLA alleles known to date. Our findings demonstrate the first example of three different HLA-Cw-determined subtypes of a common or CEH carrying a shared HLA-B allele, in this case HLA-B*4403.

Polymorphisms within the tumor necrosis factor and lymphotoxin-alpha genes and endemic pemphigus foliaceus--are there any associations?

The purpose of this study was to analyze the possible influence of the TNF and LTA loci polymorphisms on the susceptibility/resistance to endemic pemphigus foliaceus, also named fogo selvagem (FS), an autoimmune disease characterized by blisters due to acantholysis of the superficial-most epidermal cells. Autoantibodies, mainly of the IgG4 subclass, are directed against a desmosomal glycoprotein known as desmoglein 1. FS shares clinical, histological and immunological features with nonendemic pemphigus foliaceus. Most residents of the endemic regions do not develop the disease, and familial clustering has been documented, suggesting that host factors play a role in susceptibility. In fact, strong positive and negative associations with HLA class II genes have been reported. The TNF and LTA genes are located in the class III region of the Human Major Histocompatibility Complex. Their location, the function of their products, which are cytokines and pluripotent immunomodulators, as well as their genetic variability make them candidate genes for complex diseases with an altered immune response. A total of 162 patients and 191 controls were enrolled in this study. No significant associations were found with any one of the three LTA single nucleotide polymorphisms (SNP) analyzed (at nucleotides 249, 365, 720), nor with the TNF SNP located at positions -863 and -308. The frequency of allele TNF*238A was slightly decreased in patients (OR = 0.45). In conclusion, the results of this study indicate that genetic variability of the TNF and LTA genes does not play a major role in susceptibility/resistance to pemphigus foliaceus.

Hydrogenated dietary fat improves pork quality of pigs from two lean genotypes.

Pork quality is influenced by nutrition, genetics, management, and pork-processing procedures. Pigs of lean genotype fed diets high in unsaturated fat may have thinner, lower-quality bellies with a soft fat composition. Therefore, we investigated the effects of supplementing 5% choice white grease that had been chemically hydrogenated to iodine values of 80, 60, 40, or 20 on pork quality. Diets were fed to barrows and gilts of two genotypes (NPD [Ham-line x Manor hybrid] and PIC [406, 419, or 420 x C22]; n = 240) in a 4 x 2 x 2 factorial design. Pigs (76.8 kg of mean initial weight) were placed on test at a common age and were fed dietary treatments for 52 d. Pigs of PIC genotype were heavier at trial initiation, had higher feed intake and feed conversion ratio (F/G; P < 0.05), and greater backfat (26.3 vs. 24.0 mm; P < 0.001) and loin depth (59.0 vs. 55.3 mm; P < 0.001) compared with the NPD genotype pigs. As the iodine value of dietary fat was reduced, belly thickness increased (P < 0.05) and length decreased linearly (P < 0.05). Congruently, belly fat iodine value decreased from 73.9 to 67.4 (linear effect; P < 0.001) and belly fat C18:2 concentration declined from 20.6 to 16.3% (linear and quadratic effect; P < 0.001). The belly mono- and polyunsaturated fat ratio increased 29% as diet iodine value declined from 80 to 20 (linear and quadratic effect; P < 0.001). Further, there was a linear increase (P < 0.001) in saturated fatty acid concentration of belly fat (C14:0, C16:0, and C18:0) as dietary fat iodine value declined. Quadratic (P < 0.005) effects were detected in the level of C18:1trans as iodine value decreased from 80 to 20, paralleling dietary content. Dietary fat iodine value did not affect fat digestibility, ADFI, or F/G. Pork belly quality was improved as defined by reduced iodine value, C18:2 content, increased saturated fatty acid content, increased thickness, and decreased length as dietary iodine value decreased. Results indicate that reduction of dietary fat iodine value by chemical hydrogenation has the desirable effect of improving pork quality and does not alter growth performance.

Inheritable variable sizes of DNA stretches in the human MHC: conserved extended haplotypes and their fragments or blocks.

The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small (< 0.2 Mb) blocks of relatively conserved DNA sequence: HLA-Cw/B; TNF; complotype; and HLA-DR/DQ. Each of these small blocks is composed of two or more alleles of closely linked loci inherited as one genetic unit. We updated the concept of the conserved extended haplotype (CEH) using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units (>/= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.

Tissue typing in support of unrelated hematopoietic cell transplantation.

The success of unrelated hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies has closely paralleled development of robust typing methods for comprehensive and precise donor-recipient matching. The application of molecular methods in clinical research has led to a more complete understanding of the immunogenetic barriers involving host-vs-graft (HVG) and graft-vs-host (GVH) reactions. Along with the development of less toxic transplant regimens, advances in the prevention and treatment of graft-vs-host disease (GVHD) and in the supportive care of the transplant recipient, improved HLA matching of potential unrelated donors has led to clinical results that begin to compare favorably with that of HLA-identical sibling transplants.