Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation.

Natural killer (NK) cell alloreactivity, which may contribute to the graft-versus-leukemia (GVL) effect of allogeneic hematopoietic stem cell transplantation (HSCT), is influenced by the interaction of killer-cell immunoglobulin-like receptors (KIRs) on donor NK cells and their ligands, human leukocyte antigen (HLA) class I molecules on recipient antigen-presenting cells (APCs). Distinct models to predict NK cell alloreactivity differ in their incorporation of information from typing of recipient and donor KIR and HLA gene loci, which exist on different autosomes and are inherited independently as haplotypes. Individuals may differ in the inheritance of the 2 KIR haplotypes, A and B, or in the expression of individual KIR genes. Here, we examined the effect of KIR and HLA genotype, in both the recipient and donor, on the outcome of 86 patients with advanced hematologic malignancies who received nonmyeloablative (NMA), HLA-haploidentical HSCT with high-dose, posttransplantation cyclophosphamide (Cy). Compared to recipients of bone marrow (BM) from donors with identical KIR gene content, recipients of inhibitory KIR (iKIR) gene-mismatched BM had an improved overall survival (OS) (hazard ratio [HR]=0.37; confidence interval [CI]: 0.21-0.63; P=.0003), event-free survival (EFS) (HR=0.51; CI: 0.31-0.84; P=.01), and relapse rate (cause-specific HR, SDHR=0.53; CI: 0.31-0.93; P=.025). Patients homozygous for the KIR "A" haplotype, which encodes only 1 activating KIR, had an improved OS (HR=0.30; CI: 0.13-10.69; P=.004), EFS (HR=0.47; CI: 0.22-1.00; P=.05), and nonrelapse mortality (NRM; cause-specific HR=0.13; CI: 0.017-0.968; P=.046) if their donor expressed at least 1 KIR B haplotype that encodes several activating KIRs. Models that incorporated information from recipient HLA typing, with or without donor HLA typing, were not predictive of outcome in this patient cohort. Thus, NMA conditioning and T cell-replete, HLA-haploidentical HSCTs involving iKIR gene mismatches between donor and recipient, or KIR haplotype AA recipients of BM from KIR Bx donors, were associated with lower relapse and NRM and improved OS and EFS. These findings suggest that selection of donors based upon inhibitory KIR gene or haplotype incompatibility may be warranted.

Donor ethnicity influences outcomes following deceased-donor kidney transplantation in black recipients.

Although the majority of deceased-donor kidneys are donated after brain death, increased recovery of kidneys donated after cardiac death could reduce the organ shortage and is now a national priority. Racial disparities in donations after brain death have been well described for renal transplantation, but it is unknown whether similar disparities occur in donations after cardiac death. In this study, outcomes of adult deceased-donor renal transplant recipients included in the United Network for Organ Sharing database (1993 through 2006) were analyzed. Among black recipients of kidneys obtained after cardiac death, those who received kidneys from black donors had better long-term graft and patient survival than those who received kidneys from white donors. In addition, compared with standard-criteria kidneys from white donors after brain death, kidneys from black donors after cardiac death conferred a 70% reduction in the risk for graft loss (adjusted hazard ratio 0.30; 95% confidence interval 0.14 to 0.65; P = 0.002) and a 59% reduction in risk for death (adjusted hazard ratio 0.41; 95% confidence interval 0.2 to 0.87; P = 0.02) among black recipients. These findings suggest that kidneys obtained from black donors after cardiac death may afford the best long-term survival for black recipients.

Detecting and monitoring human leukocyte antigen-specific antibodies.

Renewed awareness of the relevance of HLA-specific antibodies to transplantation and the development of protocols to reduce or eliminate sensitization have made monitoring of antibodies and accurate interpretation of test results increasingly important. Here we review the various tests available and provide guidelines for the development of monitoring protocols.

Cross-reactive microbial peptides can modulate HIV-specific CD8+ T cell responses.

Heterologous immunity is an important aspect of the adaptive immune response. We hypothesized that this process could modulate the HIV-1-specific CD8+ T cell response, which has been shown to play an important role in HIV-1 immunity and control. We found that stimulation of peripheral blood mononuclear cells (PBMCs) from HIV-1-positive subjects with microbial peptides that were cross-reactive with immunodominant HIV-1 epitopes resulted in dramatic expansion of HIV-1-specific CD8+ T cells. Interestingly, the TCR repertoire of HIV-1-specific CD8+ T cells generated by ex vivo stimulation of PBMCs using HIV-1 peptide was different from that of cells stimulated with cross-reactive microbial peptides in some HIV-1-positive subjects. Despite these differences, CD8+ T cells stimulated with either HIV-1 or cross-reactive peptides effectively suppressed HIV-1 replication in autologous CD4+ T cells. These data suggest that exposure to cross-reactive microbial antigens can modulate HIV-1-specific immunity.

Elevated pretransplantation soluble CD30 is associated with decreased early allograft function after human lung transplantation.

Early allograft function after lung transplantation is variable. Clinical criteria have limited predictive value for early graft function. Recipient immunologic state before LTx may affect early lung function. We investigated the association between pretransplantation soluble CD30 (sCD30), a marker of Th2-type T-cell activation, and early clinical parameters of allograft function. Between September 2002 and January 2007, a total of 80 transplantations were performed at Johns Hopkins Hospital. Of the patients, 43 had a pretransplantation sCD30 level determined. Pre- and postoperative patient variables were collected, and patients were stratified into two groups: sCD30 <20 (low sCD30) and >20 (high sCD30). High sCD30 (n = 26) and low sCD30 (n = 17) groups were similar in age, gender, and ischemia time. In the high sCD30 group, a higher percentage of patients had pulmonary fibrosis and a lower percentage had emphysema. Oxygenation at 48 hours was significantly worse in the high sCD30 group as compared with the low sCD30 (p = 0.003). Moreover, prolonged intubation and 90-day mortality were greater in the high sCD30 group. This represents the first report of the use of sCD30 as a marker for early allograft function in human lung transplanation. Increased pretransplantation recipient sCD30 appears to be associated with decreased early post-transplantation gas exchange, prolonged intubation, and early mortality.