Side Effects Of Immunosuppression Research Articles

Personalized treatment in heart transplantation.

We are entering the era of personalized medicine, in which pharmacogenomics and biomarker-based assays can be used to tailor diagnostic tests and drug therapies to individual patients. This new approach to patient-specific care offers the potential to maximize the efficacy of available medical treatments while reducing the incidence of adverse side effects. Here, we present approaches to personalize the care of heart transplant recipients. Four strategies for personalized posttransplant care are described, including use of pharmacogenomic data to individualize the use of immunosuppressive drugs, immune monitoring to prevent acute rejection while reducing the long-term consequences of over immunosuppression, noninvasive surveillance for acute rejection, and targeted prophylaxis against opportunistic infections. The long-term survival of heart transplant recipients is limited by side effects of immunosuppressive drugs, including infectious complications, renal dysfunction, and malignancy. We discuss strategies to maximize the benefits of immunosuppressive and prophylactic therapies while minimizing their long-term toxicities.

Psychosocial Evaluation for First Hand Allotransplantation in Taiwan.

Hand transplantation has raised ethical and psychological concerns. Few studies have focused on reasons for not selecting candidates on waiting lists. To describe the psychosocial evaluation of referred prospective hand transplant candidates, we investigated candidate suitability by using 22-month follow-up data regarding the first hand transplant recipient in Taiwan. Pretransplant psychosocial assessments comprised an interview with 2 psychiatrists, a social worker, and a psychologist, followed by intelligence quotient scoring with the Wechsler Adult Intelligence Scale and Taiwanese Depression Questionnaire. After team member consensus, of the 20 patients referred to our team to confirm their hand transplantation suitability during April 26, 2013, to March 19, 2015, 7 potential recipients were placed on the waiting list after completing all prehand transplant evaluations. On September 3, 2014, the left distal forearm and hand of a brain-dead man was transplanted to a 45-year-old man who had undergone traumatic amputation of the distal third of his right forearm 30 years previously. During a 22-month follow-up, he complied with scheduled visits, including routine posttransplant laboratory tests, skin biopsies, and intensive physical therapy. Moreover, he overcame repeated graft rejections, bacterial and viral infections, immunosuppressant side effects, considerable economic stress, and the difficulties associated with the adhesion of hand tendons. Finally, he regained some satisfactory function of the transplanted hand. Considering posttransplantation difficulties, suitable candidates for hand transplantation should have persistent motivation, appropriate expectations, patience, immediate availability, fair intelligence, fair social functioning, and adequate economic and familial support.

Cell therapeutic approaches to immunosuppression after clinical kidney transplantation.

Refinement of immunosuppressive strategies has led to further improvement of kidney graft survival in recent years. Currently, the main limitations to long-term graft survival are life-threatening side effects of immunosuppression and chronic allograft injury, emphasizing the need for innovative immunosuppressive regimens that resolve this therapeutic dilemma. Several cell therapeutic approaches to immunosuppression and donor-specific unresponsiveness have been tested in early phase I and phase II clinical trials in kidney transplantation. The aim of this overview is to summarize current cell therapeutic approaches to immunosuppression in clinical kidney transplantation with a focus on myeloid suppressor cell therapy by mitomycin C-induced cells (MICs). MICs show great promise as a therapeutic agent to achieve the rapid and durable establishment of donor-unresponsiveness in living-donor kidney transplantation. Cell-based therapeutic approaches may eventually revolutionize immunosuppression in kidney transplantation in the near future.

Breakage and retention of thoracic paravertebral catheter: a case report

BackgroundParavertebral catheters are generally inserted and removed without complications. However, catheter breakage occurs rarely. This is the first report describing breakage of a thoracic paravertebral catheter and retention of the catheter fragment within the patient.Case presentationA 65-year-old female patient complained of an unusual sensation in her back during postoperative chemotherapy for lung cancer. A catheter fragment was identified in the soft tissues of the back on computed tomography. The paravertebral catheter had been placed 2 years prior left lower lobectomy. The patient had neither neurological symptoms nor infection signs around the fragment. However, the potential side effects of chemotherapy, including coagulopathy and immunosuppression, increased the risk of late-onset hematoma and abscess formation around the fragment. Therefore, we surgically removed the catheter fragment. Analysis of the fragment revealed that the catheter had been severed by the cutting edge of the Tuohy needle or the suture needle.ConclusionIn this report, a paravertebral catheter fragment was retained in the posterior mediastinum for 2 years. The catheter was likely damaged during the insertion procedure. We suggest that catheters should not be withdrawn through the Tuohy needle, but be withdrawn together with the Tuohy needle. Although secure fixation of the catheter can be achieved with sutures, to reduce the risk of damage to the catheter, alternative methods, such as surgical tapes or skin glue should be considered. After removal of a catheter, its tip should be checked to ensure that the entire catheter has been completely removed. If a catheter fragment is retained within the patient, removal of the fragment should be considered according to the patient’s condition and risks.

Hand Transplantation versus Prosthetic Substitution in Upper Extremity Amputees: Current Practice and Future Prospects

Hand transplantation and prosthetic substitution are the only two concepts available to restore hand function after hand loss. However, the indication for either technique must be carefully weighed for each patient. Recent investigations have shown no significant difference between transplanted and prosthetic hands in below elbow amputees. Thus, treatment should be guided by what is most beneficial for the patient with the least risk of harm. Due to frequently encountered side effects of immunosuppression the indication for allotransplantation must still be restrictive, the best being bilateral hand loss.

Functional and Psychosocial Outcomes of Hand Transplantation Compared with Prosthetic Fitting in Below-Elbow Amputees: A Multicenter Cohort Study.

BackgroundHand-transplantation and improvements in the field of prostheses opened new frontiers in restoring hand function in below-elbow amputees. Both concepts aim at restoring reliable hand function, however, the indications, advantages and limitations for each treatment must be carefully considered depending on level and extent of amputation. Here we report our findings of a multi-center cohort study comparing hand function and quality-of-life of people with transplanted versus prosthetic hands.MethodsHand function in amputees with either transplant or prostheses was tested with Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP) and the Disabilities of the Arm, Shoulder and Hand measure (DASH). Quality-of-life was compared with the Short-Form 36 (SF-36).ResultsTransplanted patients (n = 5) achieved a mean ARAT score of 40.86 ± 8.07 and an average SHAP score of 75.00 ± 11.06. Prosthetic patients (n = 7) achieved a mean ARAT score of 39.00 ± 3.61 and an average SHAP score of 75.43 ± 10.81. There was no significant difference between transplanted and prosthetic hands in ARAT, SHAP or DASH. While quality-of-life metrics were equivocal for four scales of the SF-36, transplanted patients reported significantly higher scores in “role-physical” (p = 0.006), “vitality” (p = 0.008), “role-emotional” (p = 0.035) and “mental-health” (p = 0.003).ConclusionsThe indications for hand transplantation or prosthetic fitting in below-elbow amputees require careful consideration. As functional outcomes were not significantly different between groups, patient’s best interests and the route of least harm should guide treatment. Due to the immunosuppressive side-effects, the indication for allotransplantation must still be restrictive, the best being bilateral amputees.

Population pharmacokinetics of mycophenolic acid and its glucuronide metabolite in lung transplant recipients with and without cystic fibrosis

1. Cystic fibrosis (CF) is a disease affecting multiple organs that may reduce the systemic exposure of some drugs. The objective of this work was to characterize and compare the population pharmacokinetics (PK) of the immunosuppressant mycophenolic acid (MPA), and its glucuronide metabolite (MPAG) in adult lung transplant recipients with and without CF (NCF) following repeated oral administration of the prodrug mycophenolate mofetil (MMF).2. A population PK model was developed, with simultaneous modeling of MPA and MPAG, using nonlinear mixed effects modeling. MPA and MPAG serum concentration-time data were adequately described by a compartmental model including enterohepatic recirculation (EHR). Both MPA and MPAG apparent clearance values were significantly elevated (>65%) in patients with CF (24.1 and 1.95 L/h, respectively) compared to the values in the NCF patients (14.5 and 1.12 L/h, respectively), suggesting a notable influence of CF on MPA absorption and disposition.3. The population PK model developed from our study successfully characterized the absorption, distribution, elimination and EHR of MPA and the metabolite MPAG in lung transplant recipients with or without CF. This model may help to further understand the impact of CF to the overall clinical effects of MPA therapy including immunosuppression and gastrointestinal side effects.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

Kidney transplant recipients' attitudes about using mobile health technology for managing and monitoring medication therapy

ObjectivesTo assess smartphone ownership, use of mobile health (mHealth) applications, and willingness to use this technology to facilitate medication management after kidney transplantation. MethodsA survey was developed with the use of previously validated questions and administered to stable adult kidney recipients from May to July 2015. Descriptive and comparative statistics were used to assess willingness to utilize mHealth technology as it related to sociodemographics, medication adherence, and medication side effects. Comparisons were also made to a survey administered in 2012. The primary outcome was the incidence of cell phone and smartphone ownership, willingness to use mHealth, immunosuppressant side effects, and self-reported nonadherence. ResultsA total of 142 patients were approached, and 139 (98%) agreed to participate; 96% of respondents indicated mobile phone ownership, 61% owned a smartphone, 30% had prior knowledge of mHealth, and 7% were already using an mHealth app; 78% reported a positive attitude toward the use of mHealth for medication management. Smartphone ownership has nearly doubled since 2012 (61% vs. 35%; P <0.001). Patients <55 years of age were more likely to own smartphones (75% vs. 46%; P <0.001) and to strongly agree with the use of mHealth (62% vs. 36%; P = 0.015). Self-reported nonadherence or severe medication side effects did not appreciably influence a patient's willingness to use mHealth. ConclusionAmong recipients of kidney transplants, smartphone ownership has dramatically increased, and recipients have a positive attitude toward the use of mHealth for medication management.

Monitoring of CD8(+) T-cell Activity in mTOR Inhibitor-treated Cancer Patients for Successful Immunotherapy

Mammalian target of rapamycin (mTOR) inhibitors are strong anti-tumor drugs; however, they have adverse immunosuppressive side effects in some cancer patients. Animal studies have provided evidence that mTOR inhibitors improved tumor-specific T-cells adoptive transfer in which the quality of CD8+ T-cells is a major factor for predicting success. Interestingly, mTOR inhibitors are capable of stimulating cytotoxic CD8+ T-cell if their dose/duration is adjusted. Rapamycin-induced CD8+ T-cells have also been associated with tumor immunity in animal models. We hypothesize that mTOR inhibitors can be a potential tool toward successful immunotherapy in cancer patients. CD8+ T-cell activity should be monitored before and after treatment to identify patients with improved CD8+ T-cells who might further benefit from expanding these cells and autologous lymphocyte therapy. Patients with a suppressed CD8+ T-cell activity may require individual adjustment of the drug dose in order to convert harmful immunosuppressive side effects of mTOR inhibitors into helpful immunostimulastory activities. Further investigations and clinical trials are required to prove the utility of CD8+ T-cell monitoring for successful immunotherapy in mTOR inhibitortreated cancer patients.

Cardiac Allograft Vasculopathy: What We Know in 2016

Cardiac allograft vasculopathy (CAV) is an immune and nonimmune-mediated process in which heart transplantation patients develop neointimal proliferative hyperplasia of the coronary arteries, typically starting distally and resulting in diffuse luminal narrowing. Risk factors include traditional coronary risk factors often resulting from side effects of immunosuppressive drugs, infection by cytomegalovirus and rejection, particularly antibody-mediated. Despite the advent of effective immunosuppression, CAV remains the primary cause of long-term mortality for heart transplant recipients. Patients undergo routine protocol surveillance for CAV after transplant, and various noninvasive and invasive diagnostic approaches can be employed in suspected CAV. Therapy is aimed primarily at prevention, given the incurable nature of CAV. The mainstay preventive therapies include statins and anti-proliferative immunosuppressive agents. In patients who develop CAV, treatment includes percutaneous coronary intervention and even retransplantation as CAV can result in irreversible systolic dysfunction and/or restrictive cardiomyopathy. This critical review aims to summarize our current knowledge of risk factors, diagnostic strategies, and therapy for CAV in heart transplant patients.

Long-term treatment of hairy cell leukemia with interferon-α: still aviable therapeutic option.

SummaryClassic hairy cell leukemia (HCL) is a rare indolent B‑cell-lymphoproliferative disorder, first described as a distinct disease entity in 1958. After more than two decades without effective chemotherapeutic options and a dismal prognosis of less than 5 years, only the introduction of interferon‑α (IFN‑α) allowed for response rates between 80–90 % and survival improvement. Nowadays, however, patients are rarely treated with IFN-α as purine analogues were found to be highly effective in HCL facilitating a near normal life span in most cases. Moreover, novel therapeutic tools for patients with relapsed or refractory disease after purine analogues have emerged such as rituximab and, more recently, vemurafenib. In the absence of long-term safety data for these novel agents, however, IFN-α may still represent a viable therapeutic option when the profound immunosuppressive side effects of purine analogues are to be avoided. We herein report a HCL patient, who has received multiple lines of therapy, including pentostatin, cladribine, and a total of 164 months of treatment with IFN‑α yielding long-term disease control. Our case illustrates that long-term administration of IFN-α with adequate dose-adjustments according to toxicity and disease activity is feasible in HCL and may still be a viable therapeutic option when purine analogues are considered unsuitable.

Is There a Role for the Enteral Administration of Serum-Derived Immunoglobulins in Human Gastrointestinal Disease and Pediatric Critical Care Nutrition?

Twenty years ago, there was profound, international interest in developing oral human, bovine, or chicken egg-derived immunoglobulin (Ig) for the prevention and nutritional treatment of childhood malnutrition and gastrointestinal disease, including acute diarrhea and necrotizing enterocolitis. Although such Ig products were shown to be effective, with both nutritional and antidiarrheal benefits, interest waned because of their cost and because of the perceived risk of bovine serum encephalitis (BSE). BSE is no longer considered a barrier to use of oral Ig, because the WHO has declared the United States to be BSE-free since the early 2000s. Low-cost bovine-derived products with high Ig content have been developed and are regulated as medical foods. These new products, called serum bovine Igs (SBIs), facilitate the management of chronic or severe gastrointestinal disturbances in both children and adults and are regulated by the US Food and Drug Administration. Well-established applications for use of SBIs include human immunodeficiency virus (HIV)-associated enteropathy and diarrhea-predominant irritable bowel syndrome. However, SBIs and other similar products could potentially become important components of the treatment regimen for other conditions, such as inflammatory bowel disease, by aiding in disease control without immunosuppressive side effects. In addition, SBIs may be helpful in conditions associated with the depletion of circulating and luminal Igs and could potentially play an important role in critical care nutrition. The rationale for their use is to facilitate intraluminal microbial antibody coating, an essential process in immune recognition in the gut which is disturbed in these conditions, thereby leading to intestinal inflammation. Thus, oral Ig may emerge as an important "add-on" therapy for a variety of gastrointestinal and nutritional problems during the next decade.

Immunoisolation to prevent tissue graft rejection: Current knowledge and future use.

This review focuses on the concept of immunoisolation and how this method has evolved over the last few decades. The concept of immunoisolation came out of the need to protect allogeneic transplant tissue from the host immune system and avoid systemic side effects of immunosuppression. The latter remains a significant hurdle in clinical translation of using tissue transplants for restoring endocrine function in diabetes, growth hormone deficiency, and other conditions. Herein, we review the most significant works studying the use of hydrogels, specifically alginate and poly (ethylene glycol), and membranes for immunoisolation and discuss how this approach can be applied in reproductive biology.

Well, I Wouldn't be Any Worse Off, Would I, Than I am Now? A Qualitative Study of Decision-Making, Hopes, and Realities of Adults With Type 1 Diabetes Undergoing Islet Cell Transplantation.

BackgroundFor selected individuals with type 1 diabetes, pancreatic islet transplantation (IT) prevents recurrent severe hypoglycemia and optimizes glycemia, although ongoing systemic immunosuppression is needed. Our aim was to explore candidates and recipients' expectations of transplantation, their experience of being on the waiting list, and (for recipients) the procedure and life posttransplant.MethodsCross-sectional qualitative research design using semistructured interviews with 16 adults (8 pretransplant, 8 posttransplant; from 4 UK centers (n = 13) and 1 Canadian center (n = 3)). Interviews were audio-recorded, transcribed, and underwent inductive thematic analysis.ResultsInterviewees were aged (mean ± SD) 52 ± 10 years (range, 30-64); duration of diabetes, 36 ± 9 years (range, 21-56); 12 (75%) were women. Narrative accounts centered on expectations, hopes, and realities; decision-making; waiting and uncertainty; the procedure, hospital stay, and follow-up. Expected benefits included fewer severe hypoglycemic episodes, reduced need for insulin, preventing onset/progression of complications and improved psychological well-being. These were realized for most, at least in the short term. Most interviewees described well-informed, shared decision-making with clinicians and family, and managing their expectations. Although life “on the list” could be stressful, and immunosuppressant side effects were severe, interviewees reported “no regrets.” Posttransplant, interviewees experienced increased confidence, through freedom from hypoglycemia and regained glycemic control, which tempered any disappointment about continued reliance on insulin. Most viewed their transplant as a success, though several reflected upon setbacks and hidden hopes for becoming “insulin-free.”ConclusionsIndependently undertaken interviews demonstrated realistic and balanced expectations of IT and indicate how to optimize the process and support for future IT candidates.

Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease.

The main limitations to the success of transplantation are the antigraft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the antidonor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. Stem Cells 2016;34:1142-1150.

Understanding kidney transplant patients' treatment choices: The interaction of emotion with medical and social influences on risk preferences

Following renal transplantation patients experience on-going immunosuppressant medication to reduce the risk of graft rejection. Over the long term the side effects of immunosuppressive drugs may affect graft survival and significantly increase risks of cancers, stroke and cardiovascular disease. To reduce these risks research is underway to develop a biomarker test to identify those patients who are likely to be ‘tolerant’ to their graft and therefore able to reduce immunosuppression. Biomarker tests may however incorrectly identify some patients as tolerant, thus jeopardising their graft. Following a quantitative assessment of risk preferences we undertook a qualitative study to investigate the range of influences that shaped the substantial variations found in the level of risk transplant recipients were hypothetically willing to take. In-depth interviews were carried out in the United Kingdom between May 2013 and July 2014 with 24 transplant recipients all of whom had stable kidney graft function. These interviews identified a range of factors that patients take into account when making risk assessments, including familial views, trust and the ritual of ‘gift exchange’ that permeates the social space of kidney transplantation. Our data support the notion that emotion is not part of a linear process, preceding and separate to reason, but is intertwined with personal understanding and perception of risk and involves a complex interplay between different influences on decision-making. Our data also support Lupton's view that risk judgements are shared and collective rather than located within the individual and suggests that patient choice rather than involving a purely rational weighing of medical benefit is often based on influences that may not accord with the framework nor intention of medical professionals and medical research.

Bioengineered uterine tissue to support pregnancy in a rat model

Event Abstract Back to Event Bioengineered uterine tissue to support pregnancy in a rat model Mats Hellstrom1, Juan M. Moreno-Moya1, Sara Bandstein1, Eva Bom1, Randa R. El-Akouri1, Kaoru Miyazaki2, Tetsuo Maruyama2 and Mats Brännström1 1 Sahlgrenska Academy, University of Gothenburg, Dept. of Obstetrics and Gynecology, Sweden 2 School of Medicine, Keio University, Dept. of Obstetrics and Gynecology, Japan Introduction: Absolute uterine factor infertility due to congenital/surgical absence of the uterus, or due to malformation or intrauterine adhesions affects about 1:500 women. Our group reported the first ever live birth after human uterus transplantation last year and this has now been followed by more births. Thus, this previously untreatable condition can now effectively be cured although with associated problems of risky donor surgery, organ shortage and side-effects of immunosuppression. The creation of a bioengineered uterus would circumvent these issues. In our animal-based research towards a human bioengineered uterus we initially use the rat model. In this study we have explored the creation of bioengineered uterine patches for tests in vivo as a step towards the creation of a complete bioengineered uterus, but also to test this patch-concept as a way of uterine-repair of a partially defect uterus. Methods: Decellularization was achieved by whole-uterus perfusion through the uterine arteries with buffered/non-buffered Triton-X100/DMSO (Group 1/2) or sodium deoxycholate (Group 3). Recellularization was achieved by injecting GFP labelled mesenchymal stem cells and uterus primary cells into the patches (5x10mm). Three days later one patch per uterus was transplanted into SD-rats to repair created uterus defects, and 6 weeks later the animals were mated. The experiments were terminated 16-20 days after mating to assess pregnancy results (number and sites of fetuses; immunohistochemistry; qPCR). Results and Discussion: Successful recellularization was confirmed by fluorescence and immunohistochemistry, but revealed limited cell distribution. Pregnancy and fetal development was normal in Group 1 and 2, with fetal development over patch areas. Group 3 showed a significant reduction in fetal numbers and no fetal development in the graft area. qPCR and immunohistochemistry revealed uterus-like tissue in the patches, with a remodulation by infiltrating host cells. Conclusion: The functionality of the reccellularized Triton-X100/DMSO-generated scaffolds was near normal and these protocols should be explored further towards the development of bioengineered uterine patches to treat partially defect uteri. Keywords: Regenerative Medicine, Tissue Regeneration, in vivo tissue engineering, acellullar matrix Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: New Frontier Oral Topic: Biomaterials in constructing tissue substitutes Citation: Hellstrom M, Moreno-Moya JM, Bandstein S, Bom E, El-Akouri RR, Miyazaki K, Maruyama T and Brännström M (2016). Bioengineered uterine tissue to support pregnancy in a rat model. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.01405 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Mats Hellstrom Juan M Moreno-Moya Sara Bandstein Eva Bom Randa R El-Akouri Kaoru Miyazaki Tetsuo Maruyama Mats Brännström Google Mats Hellstrom Juan M Moreno-Moya Sara Bandstein Eva Bom Randa R El-Akouri Kaoru Miyazaki Tetsuo Maruyama Mats Brännström Google Scholar Mats Hellstrom Juan M Moreno-Moya Sara Bandstein Eva Bom Randa R El-Akouri Kaoru Miyazaki Tetsuo Maruyama Mats Brännström PubMed Mats Hellstrom Juan M Moreno-Moya Sara Bandstein Eva Bom Randa R El-Akouri Kaoru Miyazaki Tetsuo Maruyama Mats Brännström Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Systemic Immunosuppression in High-Risk Penetrating Keratoplasty: A Systematic Review.

Cornea transplantation has a high success rate and typically only requires topical immunomodulation. However, in high-risk cases, systemic immunosuppression can be used. We conducted a systematic review on the efficacy and side effects of systemic immunosuppression for high-risk cornea transplantation. The study population was 18 years old or older with a high-risk transplant (two or more clock hours of cornea vascularization or a previous failed graft or a graft needed because of herpes simplex keratitis). A comprehensive search strategy was performed with the help of an information specialist and content experts from ophthalmology. All study designs were accepted for assessment. Level 1 and level 2 screening was performed by two reviewers followed by data abstraction. Forest plots were created whenever possible to synthesize treatment effects. Quality assessment was done with a Downs and Blacks score. From 1,150 articles, 29 were ultimately used for data abstraction. The odds ratios (ORs) for clear graft survival in cyclosporine and controls were 2.43 (95% CI: 1.00 - 5.88) and 3.64 (95% CI: 1.48 - 8.91) for rejection free episodes. Mycophenolate mofetil (MMF) significantly improved the rejection free graft survival rates at 1 year (OR: 4.05, 95% CI: 1.83 - 8.96). The overall results suggested that both systemic cyclosporine and MMF improved 1-year rejection free graft survival in high-risk keratoplasty. Cyclosporine also significantly improved clear graft survival rates at 1 year; however, there were insufficient data to analyze the same in the MMF group. Higher quality studies are needed to understand this issue better.

Multivalent nanomaterial arrays leverage antigen specificity to modulate immune response in autoimmune disease

Event Abstract Back to Event Multivalent nanomaterial arrays leverage antigen specificity to modulate immune response in autoimmune disease Brittany L. Hartwell1, Heather Shinogle2, Bradley P. Sullivan3 and Cory Berkland1, 3, 4 1 University of Kansas, Bioengineering, United States 2 University of Kansas, Microscopy and Analytical Imaging Lab, United States 3 University of Kansas, Pharmaceutical Chemistry, United States 4 University of Kansas, Chemical and Petroleum Engineering, United States Introduction: Many current therapies for autoimmune diseases such as multiple sclerosis (MS) act through nonspecific targeting of the immune response, rendering global immunosuppression, poor efficacy, and adverse side effects. To address a pressing need for safer and more effective therapies, multivalent soluble antigen arrays (SAgAs) have been developed to induce antigen-specific tolerance in MS. SAgAs consist of a flexible hyaluronic acid (HA) linear polymer cografted with multiple copies of autoantigen (proteolipid protein peptide, PLP­139-151) and secondary inhibitory signal (ICAM-1 inhibitor peptide, LABL). These peptides are intended to target SAgA molecules to the immunological synapse, interrupting signaling between T cells and antigen presenting cells (APCs) to halt propagation of an autoimmune attack[1]-[4]. Previous in vivo studies showed SAgAs containing both signals were therapeutically effective against EAE (murine model of MS)[5]. We hypothesize SAgAs enact a therapeutic effect due to enhanced, antigen-specific binding with APCs. To investigate this hypothesis, in vitro studies were performed in a model APC system to investigate antigen-specific binding and receptor response; ex vivo studies were performed in murine splenocytes to investigate targeting of EAE immune cells. Methods: 16 kDa HA was labeled with fluorescein isothiocyanate (FITC) to form ‘fHA’, then conjugated with aminooxy-LABL and/or -PLP to achieve a valency of ~10 peptides per HA backbone. Homopolymers (fHAPLP and fHALABL) were grafted with one peptide and a heteropolymer (fSAgAPLP:LABL) was co-grafted with both peptides. Conjugation was determined by RP-HPLC. In vitro binding studies were performed in Raji B cells (APCs) using flow cytometry. Cells were primed and activated with TNF-α and PLP for 24 hours. To observe maximum binding, cells were mixed with labeled arrays immediately before injection on the cytometer and allowed to reach maximum steady state (SS). Specific binding was then determined through competitive dissociation with excess addition of unlabeled HA, PLP, or LABL. Cell binding and receptor clustering were observed in real-time by fluorescence microscopy using the CellASIC ONIX Microfluidics Platform and M04S switching plate. Ex vivo binding studies were performed in splenocytes isolated from the spleens of both healthy and sick SJL/J mice, harvested at peak of disease following in vivo EAE induction. Isolated splenocytes were stained with CD3, CD22, and CD11c antibodies to identify T cells, B cells, and dendritic cells, respectively. Binding was evaluated by flow cytometry and fluorescence microscopy, as detailed above. Results and Discussion: fSAgAPLP:LABL exhibited significantly greater binding in vitro than fHA, fHAPLP, and fHALABL. Specific binding determined by competitive dissociation was driven by PLP. Receptor clustering, observed using real-time fluorescence microscopy, is an important precursor for signaling and activation of an antigen-specific cellular response. fSAgA­­PLP:LABL induced mature receptor clustering in Raji B cells to a greater extent than fHA, fHAPLP, or fHALABL. fSAgAPLP:LABL exhibited greater binding ex vivo than other arrays and greater binding in EAE splenocytes than healthy splenocytes. Conclusions: SAgAPLP:LABL exhibited enhanced cell binding due to the presence of both PLP and LABL signals, primarily driven by the antigen. SAgAPLP:LABL binding was accompanied by progressive receptor clustering which may contribute to modulation of the immune response. Additionally, SAgAPLP:LABL exhibited greater binding with EAE splenocytes over healthy splenocytes. Leveraging enhanced, antigen-specific binding and receptor modulation, SAgAs offer a promising option for antigen-specific immunotherapy to repress autoimmune disease.