Side Effects Of Immunosuppression Research Articles

Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome.

Immunosuppressive treatment for primary membranous nephropathy in adults with nephrotic syndrome.

Hyper-Synergistic Antifungal Activity of Rapamycin and Peptide-Like Compounds against Candida albicans Orthogonally via Tor1 Kinase.

Candida albicans is a life-threatening, opportunistic fungal pathogen with a high mortality rate, especially within the immunocompromised populations. Multidrug resistance combined with limited antifungal drugs even worsens the situation. Given the facts that the current drug discovery strategies fail to deliver sufficient antifungals for the emerging multidrug resistance, we urgently need to develop novel approaches. By systematically investigating what caused the different antifungal activity of rapamycin in RPMI 1640 and YPD, we discovered that peptide-like compounds can generate a hyper-synergistic antifungal effect with rapamycin on both azole-resistant and sensitive clinical C. albicans isolates. The minimum inhibitory concentration (MIC) of rapamycin reaches as low as 2.14 nM (2-9 μg/mL), distinguishing this drug combination as a hyper-synergism by having a fractional inhibitory concentration (FIC) index ≤ 0.05 from the traditional defined synergism with an FIC index < 0.5. Further studies reveal that this hyper-synergism orthogonally targets the protein Tor1 and affects the TOR signaling pathway in C. albicans, very likely without crosstalk to the stress response, Ras/cAMP/PKA, or calcineurin signaling pathways. These results lead to a novel strategy of controlling drug resistant C. albicans infection in the immunocompromised populations. Instead of prophylactically administering other antifungals with undesirable side-effects for extended durations, we now only need to coadminister some nontoxic peptide additives. The novel antifungal strategy approached in this study not only provides a new therapeutic method to control fungal infections in rapamycin-taking immunocompromised patients but also mitigates the immunosuppressive side-effects of rapamycin, repurposing rapamycin as an antifungal agent with wide applications.

Chances and risks of sodium-glucose cotransporter 2 inhibitors in solid organ transplantation: A review of literatures.

Solid organ transplantation offers life-saving treatment for patients with end-organ dysfunction. Patient survival and quality of life have improved over the past few decades as a result of pharmacological development, expansion of the donor pool, technological advances and standardization of practices related to transplantation. Still, transplantation is associated with cardiovascular complications, of which post-transplant diabetes mellitus (PTDM) is one of the most important. PTDM increases mortality, which is best documented in patients who have received kidney and heart transplants. PTDM results from traditional risk factors seen in patients with type 2 diabetes mellitus, but also from specific post-transplant risk factors such as metabolic side effects of immunosuppressive drugs, post-transplant viral infections and hypomagnesemia. Oral hypoglycaemic agents are the first choice for the treatment of type 2 diabetes mellitus in non-transplanted patients. However, the evidence on the safety and efficacy of oral hypoglycaemic agents in transplant recipients is limited. The favourable risk/benefit ratio, which is suggested by large-scale and long-term studies on new glucose-lowering drug classes such as glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, makes studies warranted to assess the potential role of these agents in the management of PTDM.

Evaluating Treatment Preferences and Perceptions of a Prosthetic Versus a Transplanted Hand: A Conjoint Analysis-Based Study.

This study used a conjoint analysis-based survey to assess which factors are most influential when considering treatment with a prosthesis or transplant after a unilateral hand amputation. Overall, 469 respondents were recruited using Amazon Mechanical Turk and asked to assume that they experienced a hand amputation. To determine preferences for a prosthetic, respondents chose among 11 pairs of alternatives with variations in the following attributes: appearance, function, maintenance, and learning time. Respondents were then presented with descriptions of the risks and outcomes of hand transplantation. The most compelling reasons for and against a transplant were determined and characteristics predictive of support for a transplant were identified. The most important attributes for a prosthesis were "lifelike appearance" and "myolectric function." For hand transplantation, respondents were most concerned about immunosuppression side effects (n = 323, 69%) and the intense nature of surgery (n = 275, 59%), whereas the most positive benefit was the concept of the transplant being "natural" (n = 339, 72%). When faced with the choice of a hand transplant or a prosthetic, approximately 50% of respondents chose a transplantation. Younger age, previous medical experiences, a perceived "familiarity with medical issues," and the regular attendance of religious services were associated with strong support for a hand transplantation (P < 0.01). When considering a hand prosthesis, respondents are motivated most by appearance and function. Meanwhile, with hand transplantation, the risks of immunosuppression and the intense nature of surgery and recovery are predominant concerns. These findings may help inform patient-physician discussions when considering treatment after unilateral hand amputation.

PCN174 Innovative Approaches to Cancer Therapy Provision in the COVID-Era

The COVID-19 pandemic has placed an unprecedented demand on healthcare systems. Cancer therapy provision has been particularly impacted due to many therapies having immunosuppressive side effects and/or their need for hospital administration. NHS England (NHSE) and the Scottish National Cancer Advisory Medicines Group (NCMAG) have both provided interim treatment recommendations to provide direction for oncologists during this pandemic. This research evaluates these NHSE and NCMAG treatment proposals.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

Pharmacokinetic and Pharmacodynamic Considerations in Relation to Calcineurin Usage in Elderly Kidney Transplant Recipients.

This review summarizes how possible age-related changes in tacrolimus and cyclosporine pharmacokinetics and pharmacodynamics may influence drug dosing and monitoring in the elderly, and highlights how micro-sampling may be useful in this cohort in the future. Advancing biological age leads to physiological changes that can affect drug absorption, distribution, metabolism and excretion, as well as immune system responsiveness. Some studies have shown that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors, suggesting that doses may need to be lowered in elderly recipients. Only one study has examined how aging effects drug target enzyme activity and demonstrated that age does not correlate with the calcineurin inhibitor half-maximal inhibitory concentration. Several studies have shown elderly kidney transplant recipients have increased risk of both morbidity and mortality, compared to younger adults due to increased susceptibility to immunosuppressant side effects, particularly cardiovascular disease, infection and malignancy. Current immunosuppressant dosing and monitoring protocols often make no adjustments for age. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established. Blood draw by micro-sampling may be useful for drug monitoring in this cohort in the future, as blood collection is minimally invasive and less painful than venepuncture. Micro-sampling could also make further pharmacokinetic, pharmacodynamics and outcome studies in the elderly more feasible.

Hydroxychloroquine Effects on TLR Signalling: Underexposed but Unneglectable in COVID-19.

The main basis for hydroxychloroquine (HCQ) treatment in COVID-19 is the compound's ability to inhibit viral replication in vitro. HCQ also suppresses immunity, mainly by interference in TLR signalling, but reliable clinical data on the extent and nature of HCQ-induced immunosuppression are lacking. Here, we discuss the mechanistic basis for the use of HCQ against SARS-CoV-2 in a prophylactic setting and in a therapeutic setting, at different stages of the disease. We argue that the clinical effect of prophylactic or therapeutic HCQ treatment in COVID-19 depends on the balance between inhibition of viral replication, immunosuppression, and off-target side effects, and that the outcome is probably dependent on disease stage and disease severity. This is supported by the initial outcomes of the well-designed randomized controlled trials: so far, evidence for a beneficial effect of HCQ treatment for COVID-19 is weak and conflicting.

Phage display identification of immunodominant epitopes and autoantibodies in autoimmune diseases

Phage display represents an invaluable tool to study autoimmune diseases. The side effects of immunosuppressive drugs for the treatment of autoimmune diseases raise awareness of the need to explore alternative therapeutic approaches such as antibodies and peptides. Therefore, phage display is an important technique for generating such molecules, so the purpose of this review is to determine the potential advantages of this technique in the research of autoimmune diseases. Many studies have also demonstrated the efficacy of phage display in identifying immunodominant epitopes of autoimmune diseases such as Goodpasture disease, immunologic thrombocytopenia, and systemic lupus erythematosus. Phage display peptide libraries have been screened with immunopurified autoantibodies from patients with autoimmune diseases. This makes it possible to more precisely locate the autoantibody binding sites, reveal a possible epitope sharing between the host and microbe, and identify a motif that mimics an antigenic structure such as that of dsDNA. Several studies have been conducted that have investigated the effectiveness of phage display in isolating autoantibody repertoires of autoantibodies against human epitopes. This allows the identification and design of antibody fragments (e.g., Fab, scFv, sdAb) that could block the binding of autoantibodies such as the deposition of IgG in the kidney and reduce the clinical signs of disease. In conclusion, phage display helps identify common epitopes and hotspot residues that can be potential therapeutic targets for the treatment of autoimmune diseases. This leads to a better understanding of the immunopathogenesis of autoimmune diseases and the development of more specific therapeutic strategies.

Micronutrient zinc roles in adjunctive therapy for COVID-19 by enhancing patients immunoregulation and tolerance to the pathogen

SARS-CoV-2 infection (COVID-19) has caused a high number of hospitalizations and deaths. There are currently no approved antiviral drugs or vaccine options available for treatment. Patients with severe cases of COVID-19 are receiving supportive care to manage life-threatening symptoms of viral pneumonia and acute respiratory distress syndrome (ARDS). Clinical and pathological evidence suggests that patients with severe COVID-19 infections suffer from cytokine storm syndrome, which leads to unfavorable health outcomes. Unfortunately, the conventional pharmacotherapies for cytokine storm syndrome are associated with immunosuppression and various other side effects that may worsen the patients’ health status and healing capability. This study is to review the literature on how zinc status may affect susceptibility and outcomes of a viral infection, as well as to explore the possible beneficial effects of supplementing zinc to alleviate COVID-19 duration and severity. We propose zinc supplementation as a viable therapeutic approach when used alone or in combination with other drugs to combat cytokine storm syndrome in COVID-19 patients. The supplementation may be especially effective for elderly patients or patients with co-morbidity already deficient in zinc. More level I randomized controlled studies are needed to determine the clinical efficacy of zinc supplementation as a potential low-cost intervention to reduce morbidity and mortality due to pneumonia and ARDS in COVID-19 patients.

Comparison of serum monocide chemoattractant protein levels with immunosuppressive therapy protocols in patients with renal transplantation.

Renal transplantation stands out with lower cost advantages in life expectancy, quality of life and especially in the long-term perspective compared to dialysis. Having significant side effects of immunosuppressive drugs in terms of patient and graft survival limits the use of these drugs. A variety of markers are being explored to prolong the renal graft life. One of these molecules, monocide chemoattractant protein (MCP-1) is a marker involved in renal inflammation. The production of MCP-1 was blocked in kidney diseases and the disease was improved. Along with these promising developments, we decided to investigate whether there is a significant relationship between immunosuppressive therapies used in renal transplantation therapy and serum MCP-1 levels. Our study was performed in 80 patients who underwent kidney transplantation followed in Haydarpaşa Numune Training and Research Hospital. These 80 patients were examined in 4 groups as Group 1 (cyclosporin), Group 2 (tacrolimus), Group 3 (sirolimus) and Group 4 (everolimus). Serum MCP-1 levels were compared between the groups by using ELISA method. In our study, serum MCP-1 levels were significantly higher in cyclosporine and tacrolimus groups than in sirolimus (p<0.05). When calcineurin inhibitors and everolimus were compared, it was not statistically significant, although calcineurin inhibitors were higher. Understanding the role of MCP-1 in monocyte homeostasis and the effects of MCP-1 inhibition in kidney disease will help to design better diagnostic and treatment strategies in patients with inflammatory kidney disease (Tab. 2, Fig. 7, Ref. 45).

Current Assessment of Clinical Pancreatic Islet Allotransplantation

Clinical islet allotransplantation represents a minimally invasive, efficacious alternative to pancreas transplantation for restoring glycemic control and insulin independence in select patients with type 1 diabetes that is complicated by intractable impaired hypoglycemia awareness and/or severe hypoglycemic events refractory to stabilization by other means. Over the last decade, islet transplantation outcomes have steadily improved in part due to refinements in the selection of optimal donors, islet isolation techniques, safer engraftment methods, and effective immunomodulatory and anti-inflammatory therapies. Insulin independence rates at five years post-transplantation at select centers have reached parity with pancreas alone transplantation, and marked progress has been achieved in islet transplantation outcomes using single-donor pancreas. However, widespread application of the procedure is still hindered due to a limited supply of donor pancreases, inadequate engraftment, and the harmful side effects of chronic immunosuppression. Strategies to address some of these challenges involve the use of alternative sources of beta cells or islets, extrahepatic sites of implantation, encapsulation of islets and novel therapies to induce tolerance. While several countries have now transitioned islet transplantation from experimental status to a funded clinical cure for patients with brittle type 1 diabetes that cannot be stabilized by more conventional means, in the US it still awaits regulatory approval and a financial mechanism for sustainable reimbursement. This review details the history and the current status of clinical islet allotransplantation while summarizing improvements that have been made in techniques involving isolation, purification, culture and assessment of human islets as well as the islet transplantation process itself. Furthermore, it discusses the limitations encountered that prevent its widespread application, strategies that address those limitations, and last but not least, clinical trials being conducted that will help position islet transplantation as a mainstay treatment for the cure of type 1 diabetes.

Successful Treatment of Refractory Ulcerative Proctitis in a Pediatric Patient Using Topical Tacrolimus

Successful Treatment of Refractory Ulcerative Proctitis in a Pediatric Patient Using Topical Tacrolimus

Récits de vie de patients greffés rénaux : de l’entrée dans la maladie à la greffe

IntroductionIn 2018, we counted 14 291 patients on the French kidney transplantation waiting list, and 3546 grafted. The law applies the presumed consent and public surveys shows a desire for information. The objective of this research was to describe transplanted patients’ lives history in order to cope with this need for information. MethodsQualitative study, narrative inquiries, of French Auvergne-Rhône-Alpes transplanted patients’ life story, between December 2016 and February 2019. Interviews were fully transcribed and analyzed by two researchers. The sampling was defined by gender, age, dialysis time and socio-professional categories. Notification to the French data protection authority was carried out. ResultsWith the ninth interview, sufficient data was collected. The start of the disease could be insidious or brutal. All interviewees changed lifestyle habits. Sometimes, the dialysis made the recovery of certain autonomy possible, but had nutritional and organizational constraints. Transplantation, without complications, reduced significantly the burden of the disease and its treatment. The difficult and agonizing expectancy of the transplant was then replaced by the patients’ feeling of Damocles sword due to the uncertainty around the graft's life expectancy. The dialysis burdens were replaced by the immunosuppressive side effects. The patients’ dependence on the graft resonated with a moral duty towards the donor, their relatives and themselves. ConclusionRenal insufficiency comprises alternations of autonomy and dependence.

An approach for the transition from systemic immunosuppressants to dupilumab

Atopic dermatitis (AD) is a complex and heterogeneous chronic inflammatory skin disease. A subset of patients require systemic immunosuppressants including cyclosporine A (CsA), azathioprine (AZA), mycophenolate mofetil (MMF)/mycophenolic acid (MPA), and methotrexate (MTX).1 Dupilumab is the first biologic for treatment of AD, mostly started in patients with insufficient effectiveness or side effects of systemic immunosuppressants. In daily practice, approximately 65% of patients are still using systemic immunosuppressants when starting dupilumab.

Corneal Recovery Following Rabbit Peripheral Blood Mononuclear Cell–Amniotic Membrane Transplantation with Antivascular Endothelial Growth Factor in Limbal Stem Cell Deficiency Rabbits

Background: Limbal stem cell deficiency (LSCD) is a refractory ocular surface disorder characterized by progressive corneal epithelial degeneration, conjunctivalization, and neovascularization, potentially leading to blindness. There are currently no effective therapeutic options for patients experiencing routine symptomatic treatment failure. Transplantation of amniotic membrane (AM) with adherent stem cells (but not bare AM transplantation alone) has shown promise in preclinical studies for ocular surface restoration. A major limitation, however, is finding a reliable stem cell source. Stem cells can be isolated from the peripheral blood mononuclear cell (PBMC) population, and these PBMC-derived stem cells have numerous advantages over allogeneic and other autologous stem cell types for therapeutic application, including relative ease of acquisition, nonimmunogenicity, and the absence of ethical issues associated with embryonic stem cells. Experiment: We examined the efficacy of autologous PBMC-AM sheet cultures combined with postoperative antiangiogenesis treatment for corneal restoration in LSCD model rabbits. Rabbit PBMCs (rPBMCs) were isolated, labeled with EdU for in vivo tracing, and then cultured on AMs in conditioned medium before transplantation. Rabbits were transplanted with bare AMs (group 1), rPBMC-AM sheets (group 2), or rPBMC-AM sheets plus postoperative treatment with the vascular endothelial growth factor antagonist bevacizumab (group 3). Corneal opacity and neovascularization were monitored by slit-lamp imaging for 8 weeks and corneas were examined histologically at 1 and 2 months. Results: Corneal opacity decreased in all three groups over 8 weeks, but was significantly lower in group 2 and even lower in group 3. Corneal neovascularization was significantly higher in group 1 throughout the observation period, and significantly lower in group 3 than group 1 and 2 by 8 weeks post-transplant. At 4 weeks, the corneal surface completed epithelialization (although thinner than normal) in group 3 but still patchy in groups 1 and 2. By 8 weeks, the epithelium in group 3 was complete and smooth, resembling a normal epithelium. Integrin β1 as a progenitor marker was also generally higher in groups 2 and 3. Conclusions: Autologous rPBMC-AM sheets with post-transplant topical bevacizumab can effectively facilitate corneal epithelium recovery in a LSCD model, suggesting clinical utility for LSCD-related ocular surface diseases. Impact statement Limbal stem cell deficiency (LSCD) increases corneal opacity and vascularization, resulting in severe visual impairment or even blindness. Traditional surgical limbal transplant is currently the main treatment option for LSCD, but carries the risks of rejection and immunosuppressant side effects. Autologous stem cell-based therapy is a promising alternative approach, but a reliable stem cell source is a major limitation. We report that transplantation of autologous rabbit peripheral blood mononuclear cell-amniotic membrane sheets plus antivascular endothelial growth factor restored avascular transparent cornea in a rabbit LSCD model. These results demonstrate a potentially effective approach for ocular surface reconstruction in bilateral LSCD.

Current Role of Anti-Integrin Therapy in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder with multifactorial etiology. Management of IBD is divided into conventional treatment and new treatment with biologic agents. The first biologic agents used for IBD was tumor necrosis factor (TNF)-inhibitor. However, TNF-inhibitor as a biologic agent has several limitations such as low rate of clinical response and systemic immunosuppressive side effects. Anti-integrin is a recently developed biologic agent which selectively inhibits leukocyte trafficking towards site of inflammation. The inhibition is caused by blocking the actions of integrin, a cell adhesion molecules (CAMs) that is necessary for leukocyte trafficking and leukocytes express specific integrin receptors for specific organs. Therefore, use of gut-specific anti-integrin agents in IBD can selectively prevent influx of leukocytes into the intestine to reduce inflammation without reducing immune function in other locations. As a result, gut-specific anti-integrin is hypothesized to have lower risk of infections and lower risk of malignancy than TNF-inhibitor while maintaining high therapeutic benefits, making anti-integrin a promising therapy for IBD in the future.

Immunosuppression in vascularized composite allotransplant: the search for an effective and safe treatment continues.

Vascularized Composite Allotransplants (VCA) including hand, face and most recently transplants of reproductive organs represent unique, life changing procedures that have been established in centers around the world, albeit in small numbers [1]. One of the major impediments in moving VCA transplants forward has been the necessity of immunosuppression for a procedure that is life-enhancing rather than lifesaving. Indeed, side-effects of immunosuppression have been broad in VCA, just like in solid organ transplant recipients. Of additional relevance, unwanted effects of immunosuppressants may also reach a different level of concern for a life-long immunosuppression in face and hand transplantation compared to short-term treatments in temporary grafts such as uterine transplants.

Dendritic Cells Transfected with MHC Antigenic Determinants of CBA Mice Induce Antigen-Specific Tolerance in C57Bl/6 Mice.

Background Nonspecific immunosuppressive therapy for graft rejection and graft-versus-host disease (GVHD) is often accompanied by severe side effects such as opportunistic infections and cancers. Several approaches have been developed to suppress transplantation reactions using tolerogenic cells, including induction of FoxP3+ Tregs with antigen-loaded dendritic cells (DCs) and induction of CD4+IL-10+ cells with interleukin IL-10-producing DCs. Here, we assessed the effectiveness of both approaches in the suppression of graft rejection and GVHD. Methods IL-10-producing DCs were generated by the transfection of DCs with DNA constructs encoding mouse IL-10. Antigen-loaded DCs from C57BL/6 mice were generated by transfection with DNA constructs encoding antigenic determinants from the H2 locus of CBA mice which differ from the homologous antigenic determinants of C57BL/6 mice. Results We found that both IL-10-producing DCs and antigen-loaded immature DCs could suppress graft rejection and GVHD but through distinct nonspecific and antigen-specific mechanisms, respectively. Discussion. We provide data that the novel approach for DCs antigen loading using DNA constructs encoding distinct homologous determinants derived from major histocompatibility complex genes is effective in antigen-specific suppression of transplantation reactions. Such an approach eliminates the necessity of donor material use and may be useful in immunosuppressive therapy side effects prevention.

Periprosthetic and interprothetic fractures in patients with rheumatism : Characteristics of conservative and surgical treatment

Periprosthetic fractures in patients with underlying rheumatic diseases can be a special challenge depending on the extent, bone quality and septic complications. Does the underlying rheumatic disease influence the treatment strategy for periprosthetic fractures? What effect do the many extra-articular and local joint-specific rheumatic involvement patterns have on the surgical strategy? How should the potential immunosuppressive side effects of continuously new biologicals be perioperatively taken into account? How can less conspicuous infections under immunosuppression be recognized clinically and using laboratory parameters? Rheumatic disease manifestations that must be perioperatively considered are presented based on the literature. The results are supplemented by many years of experience in a hospital with more than 1500 operations on patients with an underlying rheumatic disease. The treatment of periprosthetic fractures with underlying rheumatic diseases necessitates the specific consideration of the multiple accompanying conditions. In general, extra-articular manifestations, average younger age, increased susceptibility to infections, multiple joint involvement and the basic medication must be taken into consideration. The local poorer bone quality can require an adaptation of the surgical technique. These factors are summarized in a treatment algorithm for periprosthetic fractures in patients with rheumatism taking the stability of the prosthesis, the infection status, the etiology, the localization and extent of the fracture into consideration.