Influence of donor KIR genotypes on reduced relapse risk in acute myelogenous leukemia after hematopoietic stem cell transplantation in patients with CMV reactivation.

Multiple retrospective studies have demonstrated an association between cytomegalovirus (CMV) reactivation and reduced risk of AML relapse. However, the potential mechanism explaining this association remains elusive. We investigated a homogeneous cohort of 288 adult patients with AML in remission who received allogeneic hematopoietic stem cell transplantation (HCT) from matched sibling/unrelated donors between 1995 and 2011. The 5-year cumulative incidence of relapse was greater in patients without CMV reactivation compared with those with reactivation (30.2% vs. 12.1%, p = 0.001) in a landmark analysis. In multivariate analyses CMV reactivation was independently associated with reduced relapse risk (HR: 0.49 [0.25-0.95], p = 0.036) and increased non-relapse mortality (26.5% vs. 13.1%, p = 0.002) resulting in similar 5-year overall survival (64.5% vs. 59.1%, p = 0.8). In further subgroup analyses the protective effect of CMV reactivation was significant in patients who received HCT from donors with KIR Bx compared to KIR AA (11.7% vs. 29.5%, p = 0.01). Likewise, the protective effect of CMV reactivation was more significant when the donors had 2DS1 activating KIR (11.5% vs. 30.7%, p = 0.05) compared with those without 2DS1 (14.3% vs. 27.5%, p = 0.12). Our data independently confirmed the association between CMV reactivation and AML relapse, suggesting the involvement of donor KIR genotypes and NK cell-mediated graft-versus-leukemia effect.

The association between HLA and non-Hodgkin lymphoma subtypes, among a transplant-indicated population.

Several studies have implicated HLA in non-Hodgkin lymphoma (NHL) subtype etiology. However, NHL patients indicated for stem cell transplants are underrepresented in these reports. We therefore evaluated the association between HLA and NHL subtypes among a transplant-indicated population. One thousand three hundred and sixty-six NHL patients HLA-typed and indicated for transplant at the City of Hope National Medical Center (Duarte, CA) were compared to 10,271 prospective donors. Odds ratios and 95% confidence intervals were calculated for HLA haplotype and alleles, adjusted for sex and age. The HLA-A*0201∼C*0602∼B*1302∼DRB1*0701∼DQB1*0201 haplotype was significantly associated with follicular lymphoma (FL) risk among Caucasians. Several haplotypes were associated with diffuse large B-cell lymphoma (DLBCL) risk among Caucasians, including the previously implicated DLBCL risk loci, HLA-B*0801. The HLA-A*0101 allele was also observed to be associated with mantle cell lymphoma (MCL) risk. Our results support the association between previously reported susceptibility loci and FL and suggest potentially new DLBCL and MCL risk loci.

Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status.

Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis, TP53 alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in TP53 or in any other of the high-risk genes (EZH2, ETV6, RUNX1, ASXL1: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with de novo disease despite higher-risk features. While TP53 alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.

Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses.

Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMV-seronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C+ NK cells, CD16+ Vδ2(-) γδ T cells, and conventional HCMV-specific CD8+ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals.IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

Impact of Graft-Versus-Graft Natural Killer Cell Alloreactivity on Single Unit Dominance After Double Umbilical Cord Blood Transplantation.

BACKGROUND: Natural killer (NK) cell alloreactivity is favored after double umbilical cord blood transplantation (dUCBT) in which cord blood (UCB) units and patients are often HLA class I mismatched. Generally, only 1 UCB unit persists after dUCBT. We hypothesize, that NK cell alloreactivity mediated by killer cell immunoglobulin-like receptor (KIR)-HLA interactions may explain the dominance of 1UCB unit over the other after dUCBT. METHODS: We investigated the impact of KIR NK cell alloreactivities on the dominance of 1 full UCB unit in 50 dUCBT. We analyzed the effects of the KIR/HLA genetic incompatibilities and studied cord blood cells at both the phenotypic and functional levels. RESULTS: The genetic combination of KIR3DL1 loser UCB unit/Bw4 winner UCB unit determined both the dominance of 1 UCB unit (hazards ratio, 2.88 [1.32-6.27], P = 0.0077) and correlated with an increased incidence of relapse (hazards ratio, 4.91 [1.39-17.3], P = 0.0134). It is interesting to note that cord blood cells exhibited extremely low HLA class I expression. Moreover, resting cord blood KIR3DL1 NK cells exhibited a basal alloreactivity against Bw4 target cells that increased upon activation, thus triggering death by apoptosis. CONCLUSIONS: Our unicentric study suggests, for the first time, the significant impact of KIR NK cell alloreactivity in the determination of which UCB unit will dominate in dUCBT.

New insights on the natural killer cell repertoire from a thorough analysis of cord blood cells.

Although CB NK cells are characterized as immature lymphocytes, their impressive expansion and efficient graft-versus-leukemia response have been highlighted early after UCBT. To better evaluate their potential as source of effective NK cells, we revisited the study of NK cell repertoire from a large cohort of CB samples. Our study showed that the CB NK cell repertoire appears to be constructed early, depending on KIR gene content, but not on the autologous HLA environment. NKG2A was expressed on a large proportion of CB NK cells that inversely correlated with KIR(+) NK cell frequency. Self-HLA class I molecule-educated CB KIR(+) NK cells present a lower spontaneous lysis than do their adult counterparts, which is probably related to the low expression of activating NK receptors. We describe for the first time a proliferative and cytotoxic NKG2C(+) NK cell subset representing more than 10% of CB NK cells. NKG2A strongly inhibited CB NK cell degranulation, and its coexpression on NKG2C(+) NK cells may contribute to limiting their activation. Overall, the CB NK cell repertoire is constructed early and harbors numerous functional abilities shared by adult NK cells. In addition, their naïve viral status and fast expansion confer numerous advantages in immunotherapy on CB NK cells.

Influence of Absorption, Distribution, Metabolism, and Excretion Genomic Variants on Tacrolimus/Sirolimus Blood Levels and Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non-T-carriers were associated with higher blood levels (P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 (P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1, after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM.

KIR2DS5 in the presence of HLA-C C2 protects against endometriosis.

Endometriosis is defined as the presence of functional endometrial tissue outside the uterine cavity. Several hypotheses have attempted to explain the etiology and pathogenesis of endometriosis. Recently, it has been suggested that a defect of the natural killer (NK) activity in the recognition and lysis of endometrial cells is one of the crucial points in the development of this disease. Natural killer cells can express killer immunoglobulin-like receptors (KIR), which recognize class I human leukocyte antigens on target cells. We asked whether polymorphisms in KIR, HLA-C, and HLA-B genes are risk factors for endometriosis. We tested 153 women with endometriosis diagnosed on the basis of laparoscopic and histological examination, and 213 control healthy women, who gave birth to at least one child. The frequency of KIR genes in patients was similar to that in controls except for KIR2DS5, which exerted a protective effect only in HLA-C C2-positive individuals. Moreover, KIR2DS5-positive women with endometriosis had 13 times lower chance that the disease would occupy the peritoneum than KIR2DS5- and KIR2DS4del-negative ones (OR = 0.077, P = 0.0061). Similarly, KIR2DS4del-positive endometriotic persons had 11 times lower chance for peritoneal disease (OR = 0.094, P < 0.001). Negative linkage disequilibrium between KIR2DS5 and KIR2DS4del indicates that these genes are mutually exclusive. Our data suggest that KIR2DS5 may be associated with protection from endometriosis, whereas KIR2DS4del seems to be associated with higher disease stages, possibly by exclusion of protective KIR2DS5.

Analysis of graft survival in a trial of stem cell transplant in ALS.

OBJECTIVE: The first US Food and Drug Administration-approved clinical trial to treat amyotrophic lateral sclerosis (ALS) with neural stem cell-based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord-derived neural stem cells (HSSCs) transplanted into the spinal cord in patients with ALS. METHODS: Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real-time PCR methods (qPCR). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells. RESULTS: Genomic DNA from donor HSSCs was identified in all cases, comprising 0.67-5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a "nest" of cells identified on H&E staining were XY-positive by FISH, confirming donor origin. A subset of XY-positive cells labeled for the neuronal marker NeuN and stem cell marker SOX2. INTERPRETATION: This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSCs survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients.

Two new cases of KIR3DP1, KIR2DL4-negative genotypes, one of which is also lacking KIR3DL2.

The killer immunoglobulin-like receptor (KIR) genes KIR2DL4, KIR3DL2, and KIR3DP1 are present in virtually all humans. KIR2DL4 encodes a receptor present on uterine and decidual natural killer (NK) cells and some peripheral blood NK cells. Its only known ligand is the human leukocyte antigen-G molecule expressed on extravillous trophoblasts, and on tissues in some diseases. KIR3DL2 binds HLA-A*03 and HLA-A*11 as well as HLA-B*27 dimers, and microbial CpG DNA. KIR3DP1 is a pseudogene. During our immunogenetic studies we found two individuals, one from Lower Silesia district in Poland, and another from Western Ukraine, who were reproducibly negative for KIR2DL4 and KIR3DP1 genes, using three different PCR systems. Both individuals displayed very similar genotypes, possessing only KIR3DL3, KIR2DL3, KIR2DP1, KIR2DS1, and probably a rare variant of KIR2DL1. The Pole had also KIR3DL2, which the Ukrainian was apparently lacking. The Lower Silesia has been populated after the Second World War by a remarkable percentage with displaced people from Western Ukraine, which might contribute to genetic similarity of the two individuals described here.

Ex vivo detection of CD8 T cells specific for H-Y minor histocompatibility antigens in allogeneic hematopoietic stem cell transplant recipients.

Immunologic disparities between minor histocompatibility antigen (mHAg) genes on Y (H-Y) and X (H-X) chromosomes contribute to graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects observed in male recipients of a female donor (FtoM) hematopoietic stem cell transplant (HCT). Using in silico prediction tools, a panel of HLA-A0201 restricted H-Y peptides was synthesized. Expression of CD137 was monitored on CD8(+) T cells after brief stimulation with the H-Y peptides in FtoM HLA-A0201 HCT recipients (N=29), and control groups (HLA-A0201 MtoM [N=18], non-HLA-A0201 FtoM [N=14], and HLA-A0201 female volunteers [N=25]). Specific H-Y responses were significantly greater in HLA-A0201 FtoM than controls. CD8(+) T-cell responses to novel H-Y epitopes were shared among multiple patients, showing marked CD45RA(+)CD27 cytolytic effector profiles. These data represent a proof of concept for our in silico/ex vivo CD8(+) T-cell based approach of prediction and validation of H-Y mHAgs in HCT recipients, which may facilitate prospective studies to identify targets/biomarkers of GVHD/GVL.

Genetic susceptibility to anthracycline-related congestive heart failure in survivors of haematopoietic cell transplantation.

Haematopoietic cell transplantation (HCT) survivors are at increased risk for developing congestive heart failure (CHF), primarily due to pre-HCT exposure to anthracyclines. We examined the association between the development of CHF after HCT and polymorphisms in 16 candidate genes involved in anthracycline metabolism, iron homeostasis, anti-oxidant defence, and myocardial remodelling. A nested case-control study design was used. Cases (post-HCT CHF) were identified from 2950 patients who underwent HCT between 1988 and 2007 at City of Hope and had survived ≥1 year. This cohort formed the sampling frame for selecting controls (without CHF) matched on: age, race/ethnicity, cumulative anthracycline exposure, stem cell source (allogeneic, autologous), and length of follow-up. Seventy-seven cases with pre-HCT germline DNA and 178 controls were genotyped. Multivariate analysis revealed that the odds of CHF was higher in females [Odds Ratio (OR) = 2·9, P < 0·01], individuals with pre-HCT chest radiation (OR = 4·7, P = 0·05), hypertension (OR = 2·9, P = 0·01), and with variants of genes coding for the NAD(P)H-oxidase subunit RAC2 (rs13058338, 7508T→A; OR = 2·8, P < 0·01), HFE (rs1799945, 63C→G; OR = 2·5, P = 0·05) or the doxorubicin efflux transporter ABCC2 (rs8187710, 1515G→A; OR = 4·3, P < 0·01). A combined (clinical and genetic) CHF predictive model performed better [area under the curve (AUC), 0·79] than the genetic (AUC = 0·67) or the clinical (AUC = 0·69) models alone.

Protective effect of the KIR2DS1 gene in atopic dermatitis.

Atopic dermatitis (AD) is a common skin disease of complex etiology including affected humoral and cellular immune responses. The role of NK cells in development of this disease has been recently postulated, but is still poorly documented. The current study was undertaken to determine the impact of genes for the most polymorphic NK cell receptors, known as killer cell immunoglobulin-like receptors (KIRs), on the development of AD. We compared 240 patients suffering from AD with 570 healthy controls. Frequencies of the great majority of KIR genes did not differ between patients and controls, except for KIR2DS1, whose frequency was significantly (OR=0.629, CI95% (0.45; 0.87), pcorr=0.0454) lower in patients than in controls. These results were confirmed in a second cohort of 201 patients. When both patient groups were combined and compared to the control group, the result for KIR2DS1 achieved even higher significance (OR=0.658, CI95% (0.5; 0.86), pcorr=0.0158). To the best of our knowledge, this is the first report on KIR gene contribution to AD, and to allergy in general.

Chimerism testing by quantitative PCR using Indel markers.

Engraftment monitoring is critical for patients after Hematopoietic Stem Cell Transplantation (HSCT). Complete donor chimerism is the goal; therefore, early detection of rejection and relapse is crucial for guiding the patient post HSCT treatment. Quantitative PCR for chimerism testing has been reported to be highly sensitive. In this chapter we discuss the quantitative PCR (qPCR) method using 34 Indel (Insertion and Deletion) genetic markers spread over 20 different chromosomes.

Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation.

The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient-donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non-T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P < .001). The hazard ratio of acute GVHD for white patients was significantly higher than for Japanese patients. Unexpectedly, the hazard ratio of leukemia relapse in white patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background.

Detection and preliminary characterization of CD8+T lymphocytes specific for Wilms' tumor antigen in patients with non-Hodgkin lymphoma.

Wilms' tumor antigen (WT1) is overexpressed in many different solid tumors and hematologic malignancies. However, little is known about WT1 expression or WT1-specific immune responses in patients with non-Hodgkin lymphoma (NHL). In a cross-sectional survey study, we investigated the immune recognition of WT1 by patients with NHL. Utilizing a WT1 overlapping peptide library, we discovered that a large percentage of patients with NHL of all grades maintain WT1-specific T cells. Ex vivo frequencies of these T cells measured from unfractionated samples by the CD137 activation marker assay were high in many patients (some > 1% CD8+). Using standard in vitro techniques we discovered that they were cytotoxic to WT1 peptide library-loaded T2 cells and WT1 antigen-primed autologous Epstein-Barr virus-transformed B cell lines (EBV-LCLs) and expressed interferon gamma (IFN-γ). In addition, we detected WT1 mRNA transcripts in diseased lymph node tissues of patients with NHL utilizing real-time quantitative polymerase chain reaction (RT-qPCR) technology. These results are the first example of strong T cell reactivity against WT1 in patients with NHL which also demonstrate strong cytotoxicity against peptide-loaded tumor cells. The potential for developing WT1 as a target for immunotherapy in NHL deserves further exploration.

Both the nature of KIR3DL1 alleles and the KIR3DL1/S1 allele combination affect the KIR3DL1 NK-cell repertoire in the French population.

NK-cell functions are regulated by many activating and inhibitory receptors including KIR3DL1. Extensive allelic polymorphism and variability in expression can directly alter NK-cell phenotype and functions. Here we investigated the KIR3DL1(+) NK-cell repertoire, taking into account the allelic KIR3DL1/S1 polymorphism, KIR3DL1 phenotype, and function. All 109 studied individuals possessed at least one KIR3DL1 allele, with weak KIR3DL1*054, or null alleles being frequently present. In KIR3DL1(high/null) individuals, we observed a bimodal distribution of KIR3DL1(+) NK cells identified by a different KIR3DL1 expression level and cell frequency regardless of a similar amount of both KIR3DL1 transcripts, HLA background, or KIR2D expression. However, this bimodal distribution can be explained by a functional selection following a hierarchy of KIR3DL1 receptors. The higher expression of KIR3DL1 observed on cord blood NK cells suggests the expression of the functional KIR3DL1*004 receptors. Thus, the low amplification of KIR3DL1(high) , KIR3DL1*004 NK-cell subsets during development may be due to extensive signaling via these two receptors. Albeit in a nonexclusive manner, individual immunological experience may contribute to shaping the KIR3DL1 NK-cell repertoire. Together, this study provides new insight into the mechanisms regulating the KIR3DL1 NK-cell repertoire.

Hematopoietic cell transplantation with cord blood for cure of HIV infections.

Hematopoietic cell transplantation (HCT) using CCR5-Δ32/Δ32 stem cells from an adult donor has resulted in the only known cure of human immunodeficiency virus (HIV) infection. However, it is not feasible to repeat this procedure except rarely because of the low incidence of the CCR5-Δ32 allele, the availability of only a small number of potential donors for most patients, and the need for a very close human leukocyte antigen (HLA) match between adult donors and recipients. In contrast, cord blood (CB) transplantations require significantly less stringent HLA matching. Therefore, our hypothesis is that cure of HIV infections by HCT can be accomplished much more readily using umbilical CB stem cells obtained from a modestly sized inventory of cryopreserved CCR5-Δ32/Δ32 CB units. To test this hypothesis, we developed a screening program for CB units and are developing an inventory of CCR5-Δ32/Δ32 cryopreserved units available for HCT. Three hundred such units are projected to provide for white pediatric patients a 73.6% probability of finding an adequately HLA matched unit with a cell dose of ≥2.5 × 10(7) total nucleated cells (TNCs)/kg and a 27.9% probability for white adults. With a cell dose of ≥1 × 10(7) TNCs/kg, the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities. Impetus for using CB HCT was provided by a transplantation of an adult with acute myelogenous leukemia who was not HIV infected. The HCT was performed with a CCR5-Δ32/Δ32 CB unit, and posttransplantation in vitro studies indicated that the patient's peripheral blood mononuclear cells were resistant to HIV infection.

Killer immunoglobulin-like receptor (KIR) and HLA genotypes affect the outcome of allogeneic kidney transplantation.

BACKGROUND: Recipient NK cells may detect the lack of recipient's (i.e., self) HLA antigens on donor renal tissue by means of their killer cell immunoglobulin-like receptors (KIRs). KIR genes are differently distributed in individuals, possibly contributing to differences in response to allogeneic graft. METHODOLOGY/PRINCIPAL FINDINGS: We compared frequencies of 10 KIR genes by PCR-SSP in 93 kidney graft recipients rejecting allogeneic renal transplants with those in 190 recipients accepting grafts and 690 healthy control individuals. HLA matching results were drawn from medical records. We observed associations of both a full-length KIR2DS4 gene and its variant with 22-bp deletion with kidney graft rejection. This effect was modulated by the HLA-B,-DR matching, particularly in recipients who did not have glomerulonephritis but had both forms of KIR2DS4 gene. In contrast, in recipients with glomerulonephritis, HLA compatibility seemed to be much less important for graft rejection than the presence of KIR2DS4 gene. Simultaneous presence of both KIR2DS4 variants strongly increased the probability of rejection. Interestingly, KIR2DS5 seemed to protect the graft in the presence of KIR2DS4fl but in the absence of KIR2DS4del. CONCLUSIONS/SIGNIFICANCE: Our results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis.