Effect of antibodies on endothelium.

Patients developing posttransplant antibodies against HLA and non-HLA antigens expressed by the endothelium of the graft undergo more frequent episodes of rejection and have decreased long-term graft survival. Antibodies against the endothelium can alter/damage the cells of the graft through several mechanisms. Historically, antibodies were thought to elicit endothelial cell injury via complement-dependent mechanisms.

Human leukocyte antigen antibodies in chronic transplant vasculopathy-mechanisms and pathways.

Transplant recipients exhibiting posttransplant antibodies are at a higher risk for acute and chronic antibody mediated rejection (AMR). The primary alloantigens recognized by antibodies in recipients with AMR are the highly polymorphic HLA class I and class II molecules expressed on the surface of the endothelial cells (ECs) of the graft. Traditionally, anti-HLA antibodies were thought to mediate graft injury through complement-dependent mechanisms.

KIR gene content diversity in four Iranian populations.

Killer cell immunoglobulin-like receptors (KIR) regulate natural killer cell response against infection and malignancy. KIR genes are variable in the number and type, thereby discriminating individuals and populations. Herein, we analyzed the KIR gene content diversity in four native populations of Iran.

A novel duplex SSP-PCR typing method for KIR gene profiling.

Killer-cell immunoglobulin-like receptors (KIR) control the function of natural killer cells. The number and type of KIR genes are substantially variable among individuals. Sequence-specific primer-directed polymerase chain reaction (SSP-PCR) based genotyping is the most commonly used method to assess the KIR gene content.

For an always promising transplant prediction, call ANN.

With apologies to Sherlock Holmes, "You can never foretell when any one man's kidney transplant will fail, but you can say with precision when an average number will fail. ..

Variable interactions of recipient killer cell immunoglobulin-like receptors with self and allogenic human leukocyte antigen class I ligands may influence the outcome of solid organ transplants.

Purpose Of Review: The present review summarizes the diversity of killer cell immunoglobulin-like receptors and their complex interactions with self human leukocyte antigen class I molecules that control natural killer cell function. Further, a working model has been developed illustrating the potential impact of variable killer cell immunoglobulin-like receptor-human leukocyte antigen interactions on the outcome of solid organ transplants in view of current knowledge from basic and clinical research.

Recent Findings: In addition to restraining natural killer cell function, the interaction of inhibitory receptors with cognate human leukocyte antigen class I ligands has been recently shown to set the functional threshold for natural killer cells.

KIR2DL5 alleles mark certain combination of activating KIR genes.

Killer cell Ig-like receptors (KIR) control the immune response of NK cells and some T cells to infections and tumors. KIR genes evolve rapidly and are variable between individuals in their number, type and sequence. Here, we determined the nature of KIR2DL5 gene polymorphism in four ethnic groups using direct DNA sequencing method.

Distinct diversity of KIR genes in three southern Indian populations: comparison with world populations revealed a link between KIR gene content and pre-historic human migrations.

By interacting with polymorphic HLA class I molecules, the killer cell immunoglobulin-like receptors (KIR) influence the innate and adaptive immune response to infection. The KIR family varies in gene content and sequence polymorphism, thereby, distinguishing individuals and populations. To investigate KIR diversity in the earliest settlers of India, we have characterized the KIR gene content in three Dravidian-speaking populations (Mollukurumba, Kanikar, and Paravar) from the state of Tamil Nadu, southern India.

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway.

The aim of this study was to characterize the interaction between mTOR and ERK in primary endothelial cells (EC) following MHC class I and integrin ligation. Ligation of MHC class I molecules or integrins on the surface of EC leads to phosphorylation of ERK at Thr202/Tyr204. We utilized small interfering RNA (siRNA) blockade of mTOR and proteins involved in mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) to define a relationship between mTOR and ERK following MHC class I signaling.

Anti-MHC class I antibody activation of proliferation and survival signaling in murine cardiac allografts.

Anti-MHC class I alloantibodies have been implicated in the process of acute and chronic rejection because these Abs can bind to endothelial cells and transduce signals leading to the activation of cell survival and proliferation pathways. To characterize the role of the MHC class I-signaling pathway in the pathogenesis of Ab-mediated rejection, we developed a mouse vascularized heterotopic cardiac allograft model in which B6.RAG1 KO hosts (H-2K(b)/D(b)) received a fully MHC-incompatible BALB/c (H-2K(d)/D(d)) heart transplant and were passively transfused with anti-donor MHC class I Ab.

Kidney transplantation in the United States.

This chapter summarizes data on 159,119 deceased donor (DD) and 83,471 living donor (LD) kidney transplants reported to the OPTN/ UNOS registry during the 20-year period between 1988 and 2007. The 15-year graft survival rates for transplants performed during 1991-1995 were 25% for 32,327 DD and 40% for 13,992 LD recipients. Graft survival rates improved modestly (4% for DD and 2% for LD) transplants performed during 1996-2005.

Role of anti-MHC class I antibody in facilitating transplant accommodation.

The ligation of MHC class I molecules by class I antibodies on endothelial cells leads to both proliferation and survival signal transduction. This signaling pathway has been implicated in the development of acute and chronic antibody-mediated rejection. The ability of a graft to acquire resistance to immune-mediated graft injury is the basis of accommodation.

Killer cell immunoglobulin-like receptors influence the innate and adaptive immune responses.

Natural killer (NK) cells are a subset of lymphocytes which play a crucial role in early innate immune response against infection and tumor transformation. Furthermore, they secrete interferon- (IFN-) and tumor necrosis factor (TNF) prompting adaptive immunity. NK cells distinguish the unhealthy cells from the healthy ones through an array of cell-surface receptors.

Chain-terminating natural mutations affect the function of activating KIR receptors 3DS1 and 2DS3.

To determine the nucleotide polymorphism of activating killer-cell immunoglobulin-like receptors (aKIR) 3DS1 and 2DS3, we developed a novel direct-sequencing method and analyzed DNA samples of 175 KIR3DS1(+) individuals and 72 KIR2DS3(+) individuals from the white population. The putative ligand-binding extracellular immunoglobulin (Ig)-like domains of these aKIR receptors are highly conserved, a scenario contrary to inhibitory KIRs that recognize polymorphic human leukocyte antigen (HLA) class I molecules. Null alleles 3DS1*049N and 2DS3*003N that do not express cell-surface receptors were discovered, and they occur commonly in whites (3DS1*049N = 2%; 2DS3*003N = 0.

Revisiting the center effect.

Based on a model analyzing multiple effects, center variations in one-year outcomes from the OPTN/ UNOS Transplant Registry were used to estimate scores for 246 centers reporting 40+ renal transplants during 1995-2005. The adjusted one-year graft survival (derived from scores and 5 fundamental covariates) varied from 72% to 99%, demonstrating that the center effect is still the most influential factor in early renal graft survival. The 5 fundamental variables (recipient/ recipient's pre-transplant waiting time, original disease, age and degree of sensitization (PRA), proportions of expanded versus standard criteria donor grafts, donor age, cold ischemia time, transplant CMV and flow cytometry crossmatch statuses, and type of induction therapy.

The OPTN/UNOS Renal Transplant Registry.

The 10-year graft survival rates for first renal transplants performed during 1990-1994 and 1995-1999 and reported to the OPTN/UNOS Renal Transplant Registry increased from 57-58% for living donor transplants, from 42-46% for deceased donors aged 60 or under, and from 22-28% for donors over age 60 comparing the 2 intervals. These modest increases were accompanied by a 2% decline in 10-year patient survival for recipients of living and younger deceased donor grafts and a 1% improvement in patient survival for recipients of older donor kidneys. The 5-year graft and patient survival rates for transplants performed between 2000 and 2004 were 80% and 90% for living donor, 69% and 90% for standard criteria deceased donor and 55% and 82% for expanded criteria donor transplants, respectively.

Receptor-ligand analyses define minimal killer cell Ig-like receptor (KIR) in humans.

Interactions between inhibitory killer cell immunoglobulin-like receptors (iKIR) and human leukocyte antigen (HLA) class I molecules regulate natural killer (NK) cell responses to eliminate infected and transformed cells while maintaining tolerance to healthy cells. Unlinked polymorphic gene families encode KIR receptors and HLA class I ligands and their independent segregation results in a variable number and type of iKIR + HLA pairs inherited in individuals. The diversity in the co-inheritance of iKIR + HLA pairs and activating KIR (aKIR) genes in 759 unrelated individuals from four ethnic populations was analyzed.

Anti-HLA antibodies can induce endothelial cell survival or proliferation depending on their concentration.

Patients exhibiting a humoral immune response to the transplanted organ are at increased risk of antibody-mediated rejection and development of transplant vasculopathy. Historically, antibodies were thought to elicit transplant rejection through complement mediated damage of the endothelium of the graft. More recently, studies from our laboratory and others have shown that antibody ligation of class I molecules on the surface of endothelial cells transduces signals resulting in functional changes including expression of cell survival proteins and cell proliferation.

Phosphorylated S6 ribosomal protein: a novel biomarker of antibody-mediated rejection in heart allografts.

We tested the hypothesis that phosphorylation of S6 ribosomal protein (S6RP), a downstream target of the PI3K/Akt/mTOR pathway, is a biomarker of antibody-mediated rejection (AMR) in heart allografts. Primary cultures of human aortic and microvascular endothelial cells (EC) were treated with anti-HLA class I and class II antibodies (Ab) and cell lysates were studied for phosphorylation of S6 ribosmal protein at Serine235/236 (p-S6RP). Treatment of cultured EC with anti-class I and class II Ab stimulated S6RP phosphorylation.

Explainable variation in renal transplant outcomes: a comparison of standard and expanded criteria donors.

In 2002, OPTN/UNOS altered kidney allocation rules to allow patients to be listed separately to receive kidneys from expanded criteria donors (ECD). Our aim was to quantify the short- and long-term impacts of 21 prognostic factors on recipients of ECD as well as recipients of living (LD) and deceased standard criteria (SCD) donors. A factor's impact depends on both the risk and diversity of its effects.

The OPTN/UNOS renal transplant registry.

This chapter summarizes analyses of 66,843 kidney-only transplants reported to the OPTN/UNOS Renal Transplant Registry between January 1999-December 2003. The 5- and projected 10-year graft survival rates for 28,260 recipients of living donor (LD) kidneys were 80.5% and 67.

Could more effective use of kidneys recovered from older deceased donors result in more kidney transplants for older patients?

In the face of a severe shortage of kidneys from deceased organ donors that limits access to transplantation for many patients, about one of every seven kidneys (more than 1,500 each year) recovered from deceased donors in the United States are not transplanted. Eurotransplant, which coordinates organ distribution for six countries and a population of about 118 million, discards only one of every 20 kidneys procured for transplantation. We compared kidney procurement, transplants, and discards between January 2000 and June 2003 in the United States and in the Eurotransplant region using the Organ Procurement and Transplantation Network/United Network for Organ Sharing and Eurotransplant databases to examine differences that might account for this wide disparity.

A novel flow assay for the detection of cytokine secreting alloreactive T cells: application to immune monitoring.

The direct and indirect allorecognition pathways play an important role in graft rejection. We hypothesized that the presence of alloreactive memory T cells in the recipient's circulation increases the risk of rejection after transplantation. The objective of this study was to develop a noninvasive, immune monitoring tool that simultaneously measures donor-specific responses via both the direct and indirect recognition pathways.

Preformed cytotoxic antibodies in potential allograft recipients: recent data.

Presensitization to donor human leukocyte antigen (HLA) remains a major barrier to cell and organ transplantation, thereby contributing to patient mortality. The risks associated with transplantation in the presence of preformed antidonor HLA antibodies range from hyperacute rejection and increased frequency and severity of rejection to no appreciable effect on transplant outcome. Recent evidence has emphasized the importance of immunologic history, anti-HLA antibody class and titer, and differential organ susceptibility to antibody-mediated damage to explain differences in risk for antibody-mediated rejection.