Donor-recipient sex mismatch in kidney transplantation.

Background: The lack of reliable human proxies for minor (ie, non-HLA) histocompatibility loci hampers the ability to leverage these factors toward improving transplant outcomes. Despite conflicting reports of the effect of donor-recipient sex mismatch on renal allografts, the association between acute rejection of renal allografts and the development of human alloantibodies to the male H-Y antigen suggested to us that donor-recipient sex mismatch deserved re-evaluation.

Objective: To evaluate whether the relationships between donor sex and allograft failure differed by recipient sex.

Validity of surrogate measures for functional nephron mass.

Background: Transplanted nephron mass is an important determinant of long-term allograft survival, but accurate assessment before organ retrieval is challenging. Newer radiologic imaging techniques allow for better determination of total kidney and cortical volumes.

Methods: Using volume measurements reconstructed from magnetic resonance or computed tomography imaging from living donor candidates, we characterized total kidney (n=312) and cortical volumes (n=236) according to sex, age, weight, height, body mass index (BMI), and body surface area (BSA).

Short tandem repeat and human leukocyte antigen mutations or losses confound engraftment and typing analysis in hematopoietic stem cell transplants.

Clonal chromosomal abnormalities are often found in the tumor cells of patients with malignancies. These abnormalities can cause downregulation of human leukocyte antigen (HLA) and instability of short tandem repeat (STR) DNA sequences, confounding HLA typing and/or engraftment analysis in hematopoietic stem cell transplants (HSCT). We describe here the abnormalities observed during testing of 600 HSCT patients.

Donor-specific antibody against denatured HLA-A1: clinically nonsignificant?

Pre-transplant screening of a woman with end-stage renal disease (ESRD) showed no anti-human leukocyte antigen (HLA) alloantibodies by anti-human globulin-complement-dependent cytotoxicity (AHG-CDC; class I) or enzyme-linked immunosorbent assay (class II). Following a negative AHG-CDC crossmatch, an HLA*01:01+ deceased donor (DD) kidney was transplanted in September 2005. Subsequent screening of pre-transplant serum by LABScreen Single Antigen (SA) array showed strong reactivity versus A*01:01.

H-Y antibody development associates with acute rejection in female patients with male kidney transplants.

Background: Human minor histocompatibility antigens (mHA) and clinically relevant immune responses to them have not been well defined in organ transplantation. We hypothesized that women with male kidney transplants would develop antibodies against H-Y, the mHA encoded on the Y-chromosome, in association with graft rejection.

Methods: We tested sera from 118 consecutive transplant recipients with kidney biopsies.

DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans.

The association of narcolepsy with HLA-DQB1*0602 is established in Japanese, African-Americans, European, and North American Caucasians. We examined DRB1, DRB3, DRB4, DRB5, DQA1, and DQB1 in 163 patients with centrally mediated daytime sleepiness (100 with narcolepsy) and 211 Korean controls. In this population, the DQB1*0602 association was always evident in the context of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype.

Diagnosis of transfusion-related acute lung injury: TRALI or not TRALI?

TRALI is a challenging diagnosis for both the transfusion specialist and the clinician. A Canadian consensus panel has recently proposed guidelines to better define TRALI and its implications. The guidelines recommend classifying each suspected case in one of the following 3 categories: (1) "TRALI," (2) "Possible TRALI," or (3) "Not TRALI.

Protective conditioning for acute graft-versus-host disease.

Background: Conditioning with total lymphoid irradiation plus antithymocyte serum protects mice against acute graft-versus-host disease (GVHD) after hematopoietic-cell transplantation. We tested this strategy in humans.

Methods: Thirty-seven patients with lymphoid malignant diseases or acute leukemia underwent an experimental conditioning regimen with 10 doses of total lymphoid irradiation (80 cGy each) plus antithymocyte globulin, followed by an infusion of HLA-matched peripheral-blood mononuclear cells from related or unrelated donors who received granulocyte colony-stimulating factor.

A technique of bone marrow collection from vertebral bodies of cynomolgus macaques for transplant studies.

Background: Strategies to induce donor-specific allograft tolerance are best tested in preclinical models developed in nonhuman primates (NHPs). Most protocols prepare the recipient by infusing hematopoietic cells from the donor. We report here a procedure to isolate and characterize large numbers of bone marrow cells (BMCs) from cynomolgus monkeys (cynos) that can then successfully be transplanted into conditioned recipients.

Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose.

The influence of graft composition on clinical outcomes after reduced-intensity conditioning is not well-characterized. In this report we prospectively enumerated CD34+, CD3+, CD4+, and CD8+ cell doses in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) allografts in 63 patients who received transplants following non-myeloablative conditioning with total body irradiation 200 cGy plus fludarabine as treatment for malignant diseases. Donors were HLA-identical siblings (n = 38) or HLA-matched unrelated individuals (n = 25).

Short tandem repeat analysis to monitor chimerism in macaca fascicularis.

Chimerism assessment following bone marrow transplantation (BMT) in cynomolgus monkeys (cynos) has been hampered by the lack of good engraftment markers. In human BMT, such markers have been provided by short tandem repeat (STR) loci. We tested the idea that techniques effective for detecting human STR could be readily adapted to cynos.

Variable hematopoietic graft rejection and graft-versus-host disease in MHC-matched strains of mice.

MHC typing for human hematopoietic cell transplantation (HCT) from unrelated donors is currently performed by using a combination of serologic and molecular techniques. It has been determined that allelic differences in human MHC molecules, revealed by nucleotide sequencing but not by serologic typing, substantially influence graft rejection and graft-versus-host disease, two serious complications of clinical HCT. We studied transplantation of purified hematopoietic stem cells in a series of mouse strains that were matched at the MHC but had different background genes, and we observed striking differences in engraftment resistance and graft-versus-host disease severity, both factors depending on the donor-recipient strain combination.

Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation.

Background: Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft.

Methods: Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR).

Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients.

Regeneration of hematopoiesis after allogeneic hematopoietic cell transplantation (HCT) involves conversion of the recipient's immune system to donor type. It is likely that distinct cell lineages in the recipient reconstitute at different rates. Dendritic cells (DCs) are a subset of hematopoietic cells that function as a critical component of antigen-specific immune responses because they modulate T-cell activation, as well as induction of tolerance.

Concurrent IVF and spontaneous conception resulting in a quadruplet pregnancy.

Blastocyst transfer of just one or two embryos has been used to help limit the number of high-order gestations. In this case report we describe the occurrence of a quadruplet pregnancy after the transfer of only two blastocysts during IVF. Sonographic examination showed four fetuses and what appeared to be quadriamniotic/quadrichorionic sacs, suggesting that a concomitant spontaneous conception had occurred.

CD31 mismatching affects marrow transplantation outcome.

Graft-versus-host disease (GVHD) complicating allogeneic bone marrow transplantation (BMT) is often attributed to mismatched minor histocompatibility antigens (mHags), which are poorly defined in humans. CD31 is a candidate human mHag relevant to acute GVHD, but reports disagree about its level of significance, the role of HLA restriction, and the relative importance of different polymorphic codons within the molecule. We therefore examined in greater detail the impact of CD31-matching on BMT outcome in a prospective study from a single institution.

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial.

Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups.

Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed.

Clinical transplantation tolerance twelve years after prospective withdrawal of immunosuppressive drugs: studies of chimerism and anti-donor reactivity.

Background: Previous studies showed the feasibility of inducing transplantation tolerance to cadaveric renal allografts in patients given pretransplant total lymphoid irradiation (TLI). Microchimerism has been theorized to be an important or necessary factor in long-term graft acceptance and tolerance in humans.

Methods: A cadaveric renal transplant recipient given pretransplant total lymphoid irradiation and withdrawn from immunosuppressive drugs more than 12 years ago was tested for microchimerism using a sensitive nested polymerase chain reaction technique, and for anti-donor reactivity using the mixed leukocyte reaction and an ELISA screen for anti-HLA antibodies.

HLA-class II genes modify outcome of Toxoplasma gondii infection.

Associations between Human Leukocyte Antigen (HLA) (i.e. human major histocompatibility complex [MHC]) genes and susceptibility to infections and inflammatory processes have been described, but causal relationships have not been proven.

Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford.

An index patient with pseudohomozygosity for factor V Leiden was identified. Each of his two children inherited a different paternal factor V allele; a daughter was heterozygous for factor V Leiden, with 100% factor V activity, and a son was heterozygous for factor V deficiency, with 50% factor V activity. Genomic DNA was obtained from family members, and the 25 factor V exons and flanking intronic regions were sequenced in the proband and confirmed in the children.

Specific sHLA in healthy donors and donor-specific sHLA in renal transplant patients.

We studied cadaver kidney transplant recipients to determine if their serum levels of donor-specific class I sHLA correlated with graft outcome. Testing of sHLA was performed by an ELISA sandwich assay using allospecific monoclonal trapping antibodies and anti-beta2-mu detecting antibody. Sufficient sHLA sensitivity (<1 ng/ml) was achieved by using two synergistic trapping antibodies.

HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group.

Narcolepsy is a neurological disorder known to be tightly associated with HLA-DQA1*0102 and DQB1*0602. In this study, we have examined if homozygosity for DQB1*0602 increases disease susceptibility and/or severity. Patients diagnosed at Stanford University (n=160) or enrolled in a multicenter clinical trial (n=509) were included in this analysis.