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Newell K.A.,Emory University | Asare A.,University of California at San Francisco | Kirk A.D.,Emory University | Gisler T.D.,University of California at San Francisco | And 11 more authors.
Journal of Clinical Investigation | Year: 2010

Establishing long-term allograft acceptance without the requirement for continuous immunosuppression, a condition known as allograft tolerance, is a highly desirable therapeutic goal in solid organ transplantation. Determining which recipients would benefit from withdrawal or minimization of immunosuppression would be greatly facilitated by biomarkers predictive of tolerance. In this study, we identified the largest reported cohort to our knowledge of tolerant renal transplant recipients, as defined by stable graft function and receiving no immunosuppression for more than 1 year, and compared their gene expression profiles and peripheral blood lymphocyte subsets with those of subjects with stable graft function who are receiving immunosuppressive drugs as well as healthy controls. In addition to being associated with clinical and phenotypic parameters, renal allograft tolerance was strongly associated with a B cell signature using several assays. Tolerant subjects showed increased expression of multiple B cell differentiation genes, and a set of just 3 of these genes distinguished tolerant from nontolerant recipients in a unique test set of samples. This B cell signature was associated with upregulation of CD20 mRNA in urine sediment cells and elevated numbers of peripheral blood naive and transitional B cells in tolerant participants compared with those receiving immunosuppression. These results point to a critical role for B cells in regulating alloimmunity and provide a candidate set of genes for wider-scale screening of renal transplant recipients.


Herold K.C.,Yale University | Gitelman S.E.,University of California at San Francisco | Ehlers M.R.,Immune Tolerance Network | Gottlieb P.A.,Aurora University | And 9 more authors.
Diabetes | Year: 2013

Trials of immune therapies in new-onset type 1 diabetes (T1D) have shown success, but not all subjects respond, and the duration of response is limited. Our aim was to determine whether two courses of teplizumab, an Fc receptor-nonbinding anti-CD3 monoclonal antibody, reduces the decline in C-peptide levels in patients with T1D 2 years after disease onset. We also set out to identify characteristics of responders. We treated 52 subjects with new-onset T1D with teplizumab for 2 weeks at diagnosis and after 1 year in an open-label, randomized, controlled trial. In the intent to treat analysis of the primary end point, patients treated with teplizumab had a reduced decline in C-peptide at 2 years (mean 20.28 nmol/L [95% CI 20.36 to 20.20]) versus control (mean 20.46 nmol/L [95% CI 20.57 to 20.35]; P = 0.002), a 75% improvement. The most common adverse events were rash, transient upper respiratory infections, headache, and nausea. In a post hoc analysis we characterized clinical responders and found that metabolic (HbA1c and insulin use) and immunologic features distinguished this group from those who did not respond to teplizumab. We conclude that teplizumab treatment preserves insulin production and reduces the use of exogenous insulin in some patients with new-onset T1D. Metabolic and immunologic features at baseline can identify a subgroup with robust responses to immune therapy. © 2013 by the American Diabetes Association.


Feng S.,University of California at San Francisco | Ekong U.D.,Northwestern University | Lobritto S.J.,Morgan Stanley | Demetris A.J.,University of Pittsburgh | And 10 more authors.
JAMA - Journal of the American Medical Association | Year: 2012

Context: Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality. Objective: To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients. Design, Setting, and Patients: Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months). Main Outcome Measures: The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection. Results: Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n=1), acute rejection (n=2), or indeterminate rejection (n=5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P=.03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P=.04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P=.03). Conclusion: In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology. ©2012 American Medical Association. All rights reserved.


Tchao N.K.,Immune Tolerance Network | Tchao N.K.,University of California at San Francisco | Turka L.A.,Immune Tolerance Network | Turka L.A.,Beth Israel Deaconess Medical Center
American Journal of Transplantation | Year: 2012

Control of the alloimmune response requires elimination and/or suppression of alloreactive immune cells. Lymphodepleting induction therapies are increasingly used to accomplish this goal, both as part of tolerance induction protocols or to reduce the requirements for maintenance immunosuppression in the peritransplant setting. However, it is well recognized that lymphopenia induces compensatory proliferation of immune cells, generally termed ''homeostatic proliferation,'' which favors the emergence of memory T cells. Paradoxically therefore, the result may be a situation that favors graft rejection and/or makes tolerance difficult to achieve or sustain. Yet all depletion is not alike, particularly with respect to the timing of reconstitution and the types of cells that repopulate the host. Thus, to design more effective induction strategies it is important to understand the homeostatic mechanisms, which exist to maintain a balanced repertoire of naïve and memory T and B cells in the periphery and how they respond to lymphodepletion. Here we will review the biology of homeostatic proliferation stimulated by lymphopenia, the effects of specific depleting agents on reconstitution of the T- and B-cell immune repertoire, drawing from both from animal models and human experience, and potential strategies to enhance allodepletion while minimizing the adverse effects of homeostatic proliferation. The authors review the biology of homeostatic proliferation stimulated by lymphopenia, the effects of specific depleting agents on reconstitution of the T and B cell immune repertoire, and potential strategies to enhance allodepletion while minimizing the adverse effects of homeostatic proliferation. © 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.


News Article | February 15, 2017
Site: www.eurekalert.org

Patients blighted by hay fever could markedly reduce symptoms for several years after a three-year course of treatment, but not after two years of treatment, researchers have found. **Case study available - see notes** Previous research has shown that a type of immunotherapy that exposes patients to increasing amounts of grass pollen over time is an effective way to reduce severe symptoms in the long term. But in a new study, published today in the journal JAMA, scientists from Imperial College London have found that a two-year course of treatment is not enough to achieve lasting effects, bolstering previous findings that more time is needed taking the medication to get lasting benefit. The research was funded by the Immune Tolerance Network, supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. "You treat patients for three years and then they have a big improvement in their hay fever for several years afterwards," said Professor Stephen Durham, Head of Allergy and Clinical Immunology at the National Heart and Lung Institute at Imperial and clinical lead for allergy services at Royal Brompton Hospital, who led the study. "Exposing people to grass pollen in this way is a very effective treatment for people who really have debilitating hay fever." Hay fever, or seasonal allergic rhinitis, affects as many as one in four people in the UK, leaving sufferers with bouts of sneezing, runny nose and itchy eyes -- all of which can affect work, school and leisure during the summer months when the pollen count soars. In the majority of cases in the UK the culprit is grass pollen, which the body recognises as an invader, launching an immune response. A number of over the counter medications are available, such as nasal sprays and antihistamine tablets, but patients with more severe symptoms can be treated with immunotherapy, using a similar approach to the one trialled in children with peanut allergies. By exposing their immune system to grass pollen extracts over time they are able to build up their resistance, either through injections or a pill containing pollen extract. The latest study involved patient volunteers at Royal Brompton Hospital in London, which runs a world-class allergy clinic, researchers tested the effectiveness of two immunotherapies prescribed by the NHS which use grass pollen extract: an injection and a pill taken under the tongue. It was the first head to head trial of the two therapies, in which researchers set out to see if a two-year treatment could achieve the same long-lasting benefits to patients as seen with three-years of immunotherapy, potentially leading to clinical cost savings. The study was a double blind, placebo-controlled trial in which 106 patients were randomised to one of three treatment groups: injection, tablets and placebo. Patients had moderate to severe hay fever and were administered either the daily oral treatment, weekly injections for 15 weeks followed by monthly boosters, or a placebo. A total of 92 patients completed the study. After a two year course of treatment, the results showed that both therapies were effective at tackling symptoms, with patients reporting a dramatic improvement in their quality of life. However, one year after patients had stopped taking the medication the effects were no better than the placebo group. "Hay fever causes major impairment of sleep, work and school performance and leisure activities during what for most of us is the best time of the year," said Professor Durham. "Most people respond to the usual antihistamines and nasal sprays, although there is a portion who do not respond adequately or who have unacceptable side effects to the treatment." Describing the current findings, Professor Durham said: "This study shows that whereas both immunotherapy treatments were highly effective, two years of treatment was insufficient for long-term benefits. "Clinicians and patients should continue to follow international guidelines that recommend a minimum of three years' treatment." Previous studies published by Imperial researchers have shown the long-lasting benefits of both immunotherapy injections and pills for severe hay fever - benefits which persist for at least two to three years after the treatment has stopped. Professor Durham added: "We have reconfirmed that both treatments are effective but that in order to get the long-term clinical benefits after stopping the treatment, you have to take it for three years." Researchers at Imperial have a long legacy with immunotherapy dating back to 1911, when a grass pollen injection treatment was first shown to be highly effective in treating hay fever. Max Warner, 51, who lives in London, had successful results in improving his symptoms of hay fever by receiving injections of grass pollen immunotherapy as part of the randomised, placebo-controlled trial over a three-year period at Royal Brompton Hospital. "I've been allergic to grass pollen ever since I can remember," explained Mr Warner. "Hay fever has a massive impact on my lifestyle and I choose to work from home because of it, I just find commuting through central London worsens my symptoms. I suffer with irritability, sneezing, wheezing and at times this can manifest into a tightened chest where I feel as if I can't breathe properly, especially during summer." Mr Warner was first tested for his sensitivity to pollen at Royal Brompton Hospital when doctor's sprayed pollen up his nose to compare his reaction before he began receiving injections to his reactions a year into receiving the hay fever treatment. He received weekly injections for 15 weeks and then monthly injections for the remainder of the two-year treatment period. "My hay fever symptoms improved over the two years of having injections and the following year as well. My hay fever season can start in April and not finish until September. May, June, July and August are obviously the peak months and these peaks took place during the trial where I felt no symptoms in April or September. "In the peak months I had less of a blocked up nose; less of a runny nose, less, if any, sneezing, no irritable or watering eyes, no tight chest and just generally much less of a sense of feeling unwell and having less energy throughout the grass pollen season. "My reaction to pollen had decreased an incredible amount," said Mr Warner. "I really did feel a huge improvement and was relieved to discover I had received the immunotherapy treatment. Last summer [after the trial had finished] I was back to taking antihistamines and was shocked with how bad my symptoms were." He added: "They are a fantastic team at Royal Brompton. Everyone who was participating felt confident that we were doing something that would make a worthwhile improvement to our health and the health of others. If I had the opportunity, I would carry on receiving the injections."


Dall'Era M.,University of California at San Francisco | Cisternas M.G.,MGC Data Services | Smilek D.E.,Immune Tolerance Network | Straub L.,Immune Tolerance Network | And 4 more authors.
Arthritis and Rheumatology | Year: 2015

Objective There is a need to determine which response measures in lupus nephritis trials are most predictive of good long-term renal function. We used data from the Euro-Lupus Nephritis Trial to evaluate the performance of proteinuria, serum creatinine (Cr), and urinary red blood cells (RBCs) as predictors of good long-term renal outcome. Methods Patients from the Euro-Lupus Nephritis Trial with proteinuria, serum Cr, and urinary RBC measurements at 3, 6, or 12 months and with a minimum of 7 years of followup were included (n=76). We assessed the ability of these clinical biomarkers at 3, 6, and 12 months after randomization to predict good long-term renal outcome (defined as a serum Cr value ≤1.0 mg/dl) at 7 years. Receiver operating characteristic curves were generated to assess parameter performance at these time points and to select the best cutoff for individual parameters. Sensitivity and specificity were calculated for the parameters alone and in combination. Results A proteinuria value of <0.8 gm/day at 12 months after randomization was the single best predictor of good long-term renal function (sensitivity 81% and specificity 78%). The addition of serum Cr to proteinuria as a composite predictor did not improve the performance of the outcome measure; addition of urinary RBCs as a predictor significantly decreased the sensitivity to 47%. Conclusion This study demonstrates that the level of proteinuria at 12 months is the individual best predictor of long-term renal outcome in patients with lupus nephritis. Inclusion of urinary RBCs as part of a composite outcome measure actually undermined the predictive value of the trial data. We therefore suggest that urinary RBCs should not be included as a component of clinical trial response criteria in lupus nephritis. © 2015, American College of Rheumatology.


Rigby M.R.,Indiana University | Ehlers M.R.,Immune Tolerance Network
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2014

Purpose of Review: Although insulin is lifesaving and sustaining for those with type 1 diabetes (T1D), curing the disease will be much more complex than simple replacement of this hormone. T1D is an autoimmune disease orchestrated by T cells, and includes many arms of the immune response. Tremendous effort has gone into understanding its underlying immune, genetic, and environmental causes, and this progress has led to immunologically based clinical trials in T1D. This review will focus primarily on the clinical trials of the past decade that have attempted to translate these fundamental findings. Recent Findings: It is known that powerful, nonspecific immune suppressants can temporarily slow the course of newly diagnosed T1D, yet are too toxic for long-term use, especially in children. Recent clinical trials to reverse T1D have used newly developed therapies that target specific components of the immune process believed to be involved with T1D. Although well justified and designed, no recent approach has resulted in clinical remission and few have had any effect on disease course. SUMMARY: Advances in our fundamental understanding of how the human diabetes immune response is activated and regulated coupled with lessons that have been learnt from the most recent era of completed trials are guiding us toward the development of more effective, multipronged therapies to ablate diabetes autoimmunity, restore immune tolerance, preserve β cells, and, ultimately, improve the lives of patients with T1D. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Shamji M.H.,Imperial College London | Layhadi J.A.,Imperial College London | Scadding G.W.,Imperial College London | Cheung D.K.M.,Imperial College London | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Immunotherapy inhibits basophil histamine release, but the assay is cumbersome, and no one has studied the effects of immunotherapy withdrawal. Objective Intracellular fluorochrome-labeled diamine oxidase (DAO) was used as a novel functional readout of basophil histamine release after immunotherapy. Results were compared with conventional basophil surface expression of activation markers. Methods Subcutaneous immunotherapy (SCIT)-treated patients (n = 14), sublingual immunotherapy (SLIT)-treated patients (n = 12), participants who completed 3 years of treatment with grass pollen sublingual immunotherapy (the SLIT-TOL group; n = 6), patients with untreated seasonal allergic rhinitis (SAR; n = 24), and nonatopic control subjects (n = 12) were studied. Intracellularly labeled DAO+ and surface expression of CD203cbright, CD63+, and CD107a+ on chemoattractant receptor-homologous molecule expressed on TH2 lymphocytes (CRTh2)-positive basophils were measured by means of flow cytometry. Serum IgG4 levels and serum inhibitory activity for IgE-allergen complex binding to B cells (IgE-FAB) and basophil histamine release were also determined. Results Proportions of allergen-stimulated DAO+CRTh2+ basophils were higher in participants in the SCIT, SLIT, and SLIT-TOL groups (all P <.0001) compared with those in patients in the SAR group. Similarly, there were lower proportions of CRTh2+ basophils expressing surface CD203cbright (all P <.001), CD63 (all P <.001), and CD107a (all P <.01). Rhinitis symptoms were lower in the SCIT, SLIT, and SLIT-TOL groups (P <.001) compared with those in the SAR group. Serum inhibitory activity for IgE-FAB and basophil histamine release were also significantly greater in all immunotherapy groups (P <.05) compared with the SAR group. Conclusion These results support long-term clinical and immunologic tolerance during and after grass pollen immunotherapy. Intracellularly labeled DAO expression by basophils merits further investigation as a surrogate biomarker for monitoring efficacy and tolerance after immunotherapy. © 2014 American Academy of Allergy, Asthma & Immunology.


Newell K.A.,Emory University | Phippard D.,Immune Tolerance Network | Turka L.A.,Immune Tolerance Network | Turka L.A.,Beth Israel Deaconess Medical Center
Current Opinion in Immunology | Year: 2011

Experimental models of transplantation provide strong support for the role of regulatory cells in tolerance. However, limited studies of humans who display sustained tolerance following transplantation have not definitively demonstrated a role for regulatory cells in this process. Rather than excluding or minimizing the contribution of regulatory cells to the development of transplantation tolerance, we suggest the possibility that multiple lineages of cells exert regulatory effects that contribute to the development of tolerance, that these regulatory effects are not constant but vary over time, and that the role of regulatory cells varies based on the organ transplanted. More detailed studies will be necessary to elucidate the role of regulatory cells in clinical transplantation and tolerance. © 2011.


News Article | February 22, 2017
Site: www.sciencemag.org

Type 1 diabetes is one of the most common serious diseases to strike young children, but how does it start? It’s a question that has bedeviled scientists for years. Now, a new study pinpoints a warning sign in healthy babies as young as 6 months old. The work could advance prevention efforts and might help explain the genesis of the autoimmune disease. Type 1 diabetes hits when the body destroys insulin-producing cells in the pancreas. By the time people—many of them children—are diagnosed, most of those cells are gone. Forty thousand new type 1 diabetes cases are recorded each year in the United States, and the disease is on the rise for reasons not well understood. A dream for diabetes researchers is to treat kids earlier, when they are headed down the diabetes road but aren’t yet there. About 3 decades ago, scientists discovered a collection of signposts: antibodies directed at certain proteins in the body, including insulin. As they studied these children more intensively, they learned that those with two or more different kinds of these autoantibodies will eventually develop diabetes, though sometimes not for many years. Many clinical trials have since focused on trying to slow disease onset in these individuals. But what happens before these autoantibodies arise? Ezio Bonifacio, a biologist at the Technische Universität Dresden in Germany, had the means to tackle this question. He and his colleagues had for years been following children since birth whose genetics and family history put them at increased risk. Beginning in 2000, the researchers began to collect and store blood cells from a subset of these children. Recently, technology had advanced to the point that scientists could analyze single cells in those samples. “We decided that it was time to start to see if there was something happening at the level of the T cells,” Bonifacio says. Commonly referred to as the sentries of our immune system, T cells are the villains in diabetes. They for some reason go rogue, leading the attack on insulin-producing cells in the pancreas. Bonifacio and his colleagues performed sophisticated analysis on T cells from 12 babies who didn’t develop autoantibodies later—suggesting they were in the clear—and 16 babies who did. Probing the T cells in the lab, they saw that cells from the children who continued down the path toward type 1 diabetes were not normal. Essentially, when the T cells were exposed to a substance called an antigen, which in this case could trigger a response against insulin-producing cells, some of those T cells got activated. This is a faint echo of what happens inside the body of someone developing diabetes: Their T cells are activated against cells in the pancreas much as they would be against a foreign invader, like a virus. “These T cells have somehow already learnt to get halfway” toward becoming autoreactive cells, says Bonifacio, whose team reports its findings today in . Bonifacio cautions that the findings are still preliminary. For one, samples like these from infancy are rare, and thus the number of children whose T cells were studied is modest. For another, although the unusual T cell behavior was entirely absent in kids who didn’t get autoantibodies later on, it was recorded in only about half who did. Still, the work breaks ground by identifying likely signs of type 1 diabetes studies earlier than ever, says Kevan Herold, an endocrinologist at Yale University, who studies ways to prevent the condition. “The value of this paper is that there’s stuff that can be measured even before” the autoantibodies, agrees Gerald Nepom, director of the Immune Tolerance Network and former director of the Benaroya Research Institute in Seattle, Washington. One central mystery is what’s causing the changes in these cells so early in life. Bonifacio and others have looked exhaustively for environmental drivers of type 1 diabetes; although there have been hints of various influences, like certain infections, “the punch line here is that the data’s inconsistent” across all the studies, says Carla Greenbaum, who chairs Type 1 Diabetes TrialNet, which oversees type 1 diabetes treatment and prevention trials, and directs the diabetes program at the Benaroya Research Institute. So diabetes experts like Greenbaum have their eyes on prevention. Bonifacio is co-leading a study called Pre-POINT-Early, which offers oral insulin to children between 6 months and 2 years old; results are expected sometime next year. An oral insulin prevention study by TrialNet, in people with autoantibodies, will be reported in June. Herold hopes to report data in the near future on a study of an antibody called anti-CD3; he has tested it in newly diagnosed patients and is now trying it as a preventive.

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