Leukofiltration plus pathogen reduction prevents alloimmune platelet refractoriness in a dog transfusion model.

Human lymphocyte antigen alloimmunization to filter leukoreduced (F-LR) platelets occurs in about 18% of immunosuppressed thrombocytopenic hematology/oncology patients and represents a significant challenge for effective chemotherapy. In a dog platelet transfusion model, we have evaluated other methods of preventing alloimmune platelet refractoriness and demonstrated that successful methods in our dog model are transferable to man. In the present study, donor/recipient pairs were dog lymphocyte antigen DR-B incompatible (88% of the pairs), and recipient dogs received up to 8 weekly treated transfusions from a single donor (a highly immunogenic stimulus), or until platelet refractoriness.

Ultraviolet B irradiation in the prevention of alloimmunization in a dog platelet transfusion model.

Background: Alloimmune platelet (PLT) refractoriness remains a significant problem for chronically transfused patients with thrombocytopenia.

Study Design And Methods: In a dog PLT transfusion model, we evaluated ultraviolet B irradiation (UV-B) of donor PLTs-either alone or in combination with centrifuge leukoreduction (C-LR) or filtration leukoreduction (F-LR)-to prevent refractoriness to donor PLTs and to induce tolerance to standard (STD) PLTs from the same donor or to tertiary donors.

Results: Recipient acceptance rates for C-LR donor PLT transfusions were 14%, F-LR were 33%, and UV-B irradiated were 45% with no significant differences among the treatments given to the donor's PLTs.

A novel JK null allele associated with typing discrepancies among African Americans.

The Jknun (Jk-3) phenotype, attributable to null or silenced alleles, has predominantly been found in persons of Polynesian descent. With the increased use of molecular genotyping, many new silencing mutations have been identified in persons of other ethnic backgrounds. To date, only two JK null alleles have been reported in African Americans, JK*01N.

Masked and overt autoantibodies specific to the DPD epitope of 65-kDa glutamate decarboxylase (GAD65-DPD) are associated with preserved β-cell functional reserve in ketosis-prone diabetes.

Context: Ketosis-prone diabetes (KPD), defined by presentation with diabetic ketoacidosis (DKA), comprises 4 subgroups based on the presence or absence of islet cell autoantibodies (A(-) or A(+)) and β-cell functional reserve (β(-) or β(+)). Among A(+) KPD, autoantibody epitope reactivity to 65-kDa glutamate decarboxylase (GAD65), defined by monoclonal GAD65Ab(DPD), was associated with greater β-cell functional reserve. In a majority of healthy individuals, GAD65Ab are present in the sera but are masked by anti-idiotypic antibodies; in contrast, overtly GAD65Ab-positive patients with autoimmune type 1 diabetes patients lack these anti-idiotypic antibodies.

Presence or absence of a known diabetic ketoacidosis precipitant defines distinct syndromes of "A-β+" ketosis-prone diabetes based on long-term β-cell function, human leukocyte antigen class II alleles, and sex predilection.

Ketosis-prone diabetes (KPD) is heterogeneous. Longitudinal follow-up revealed that patients with "A-β+" KPD (absent autoantibodies and preserved β-cell function) segregated into 2 subgroups with distinct evolution of β-cell function and glycemic control. Generalized linear analysis demonstrated that the variable that most significantly differentiated them was presence of a clinically evident precipitating event for the index diabetic ketoacidosis (DKA).

HLA class II alleles specify phenotypes of ketosis-prone diabetes.

Objective: Ketosis-prone diabetes (KPD) comprises four subgroups based on the presence or absence of beta-cell autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). Genetic factors could contribute to their distinctive phenotypes. Our aim was to specify the role of HLA class II alleles associated with susceptibility or resistance to autoimmune type 1 diabetes in determining KPD phenotypes.

Accuracy and predictive value of classification schemes for ketosis-prone diabetes.

Objective: Ketosis-prone diabetes (KPD) is an emerging, heterogeneous syndrome. A sound classification scheme for KPD is essential to guide clinical practice and pathophysiologic studies. Four schemes have been used and are based on immunologic criteria, immunologic criteria and insulin requirement, BMI, and immunologic criteria and beta-cell function (Abeta classification).

The use of CD 34(+) mobilized peripheral blood as a donor cell source does not improve chimerism after in utero hematopoietic stem cell transplantation in non-human primates.

In utero hematopoietic stem cell transplantation is a therapeutic procedure that could potentially cure many developmental diseases affecting the immune and hematopoietic systems. In most clinical and experimental settings of fetal hematopoietic transplantation the level of donor cell engraftment has been low, suggesting that even in the fetus there are significant barriers to donor cell engraftment. In postnatal hematopoietic transplantation donor cells obtained from mobilized peripheral blood engraft more rapidly than cells derived from marrow.

Fetal immune suppression as adjunctive therapy for in utero hematopoietic stem cell transplantation in nonhuman primates.

In utero hematopoietic stem cell transplantation could potentially be used to treat many genetic diseases but rarely has been successful except in severe immunodeficiency syndromes. We explored two ways to potentially increase chimerism in a nonhuman primate model: (a) fetal immune suppression at the time of transplantation and (b) postnatal donor stem cell infusion. Fetal Macaca nemestrina treated with a combination of the corticosteroid betamethasone (0.

Evaluation of different methods of leukoreduction of donor platelets to prevent alloimmune platelet refractoriness and induce tolerance in a canine transfusion model.

The effectiveness of different methods of leukoreduction in preventing alloimmune platelet refractoriness was evaluated in a canine model. Platelets from a random donor dog were administered for up to 8 weeks or until platelet refractoriness. Standard (STD; unmodified) platelets were accepted by 14% of recipients (n = 7) compared with 14% for centrifuge leukoreduced (C-LR) platelets (n = 21) and 31% for filter leukoreduced (F-LR) platelets (n = 13; no significant differences).

Nonhuman primate models for islet transplantation in type 1 diabetes research.

Insulin-dependent diabetes mellitus is an autoimmune disease that causes a progressive destruction of the pancreatic beta cells. As a result, the patient requires exogenous insulin to maintain normal blood glucose levels. Both the pancreas and the islets of Langerhans have been transplanted successfully in humans and in animal models, resulting in full normalization of glucose homeostasis.

HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms do not seem to be risk markers for severe retinopathy in younger Type 1 diabetic patients.

The aim of this study was to test the hypothesis that HLA-DRB1, -DQA1, and -DQB1 subgroups or angiotensin-converting enzyme (ACE) gene polymorphisms are associated with severe retinopathy in younger Type 1 diabetic patients. Twenty-four Type 1 diabetic patients who had received panretinal photocoagulation for severe nonproliferative or proliferative diabetic retinopathy were compared with 24 Type 1 diabetic patients (participating in a photographic screening program with regular fundus examinations) with no or minimal retinopathy, matched for age at onset and duration of diabetes. The HLA-DRB1-DQA1-B1 haplotype 04-03-0302 represented 22/48 (46%) in the severe and 21/48 (44%) in the no/minimal retinopathy group, respectively (n.

Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes.

Ketosis-prone diabetes is heterogeneous. Its causes could include novel beta-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for beta-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of beta-cell function and biochemical and clinical parameters.

In utero hematopoietic stem cell transplantation in nonhuman primates: the role of T cells.

In utero transplantation of hematopoietic stem cells is a promising treatment for immune and hematologic diseases of fetuses and newborns. Unfortunately, there are limited data from nonhuman primates and humans describing optimal transplantation conditions. The purpose of this investigation was to determine the effect of T-cell number on engraftment and the level of chimerism after in utero transplantation in nonhuman primates.

Immunogenetic correlates for Chlamydia trachomatis-associated tubal infertility.

Objective: To understand immunogenetic mechanisms of Chlamydia trachomatis infection and tubal scarring.

Methods: We measured and compared previously significant human leukocyte antigen (HLA) class II DQ alleles, their linked DRB genes, and polymorphisms in selected cytokine genes (tumor necrosis factor alpha-308 promoter; transforming growth factor beta1-10 and -25 codons; interleukin 10-1082, -819, and -592 promoters; interleukin 6-174 promoter; and interferon gamma+874 codon 1) among Kenyan women with confirmed tubal infertility with and without C trachomatis microimmunofluorescence antibody.

Results: Two class II alleles, HLA-DR1*1503 and DRB5*0101, were detected less commonly in C trachomatis microimmunofluorescence seropositive women than in C trachomatis microimmunofluorescence seronegative women with infertility (0% versus 20%; odds ratio [OR] 0.

Diabetes duration may modify the association between genetic variation in the glycoprotein Ia subunit of the platelet collagen receptor and risk of severe diabetic retinopathy: a working hypothesis.

Genetic factors appear to contribute to the severity and progression of diabetic retinopathy. We assessed the associations of the C807T and Glu505Lys variants of the glycoprotein Ia (alpha(2) integrin) subunit of the platelet/endothelial collagen receptor and risk of retinopathy in a population-based survey of 288 diabetic patients in one Swedish community. Neither variant was associated with retinopathy risk overall.

Genetic variants of the hemostatic system and development of transplant coronary artery disease.

Background: The occurrence of coronary artery disease (CAD) after heart transplantation may represent an accelerated inflammatory and thrombotic response to coronary vascular endothelial cell injury. Several common mutations involving hemostasis and cellular adhesion proteins have been associated with genetic susceptibility to native coronary heart disease. The clinical setting of heart transplantation provides a unique opportunity to examine the relative contribution of circulating (i.

Induction of islet allotolerance in nonhuman primates.

Recent clinical trials have pioneered the successful use of a nonsteroidal immunosuppressive regimen and established a basis for application in a routine clinical setting. In this study, a single islet transplant was not sufficient to regulate blood glucose levels, and a second transplant became necessary. A similar observation was made in our macaque islet transplant study, where animals after the second transplantation have shown trends towards normoglycemia in the presence of mycophenolate mofetil.

Induction of donor-specific tolerance to islet allografts in nonhuman primates.

Pancreatic tissue grafting is by far the most physiological therapeutic solution to the insulin deficiency of diabetes. Recent clinical trials have indicated somewhat successful use of nonsteroidal immunosuppressive regimens and a successful nonhuman primate trial using CD154 for costimulation blockade was reported. However, these protocols need to be replaced with safe and efficacious ones in which long-term allotolerance would make these treatments routine in a clinical setting.

ICA+ relatives with DQA1*0102/DQB1*0602 have expected 0602 sequence and DR types.

The HLA haplotype DQA1*0102/DQB1*0602 reportely confers protection from type 1 diabetes. DQA1*0102/DQB1*0602 is present in more than 7% of ICA positive relatives screened as part of the Diabetes Prevention Trial--type 1. The presence of autoantibodies in these subjects suggests that the mechanism that protects DQB1*0602 subjects from diabetes occurs after the disease process has been initiated.

Reactivity patterns of class I HLA monoclonal antibodies that distinguish three species of macaques.

The reactivity of a panel of 40 monoclonal antibodies (mAb) specific for HLA class I antigens was assessed in 117 unrelated Macaca mulatta (Mm), with a standard microcytotoxicity assay, in order to compare phenotypic frequencies with those previously reported for M. fascicularis (Mfl) and M. nemestrina (Mn).