Long-term Use Of Immunosuppressive Agents Research Articles

Identification of risk factors for disseminated cryptococcosis in non-hiv patients: a retrospective analysis

ObjectiveThis study aimed to investigate the potential risk factors associated with disseminated cryptococcosis in HIV-negative individuals.MethodsA total of 106 HIV-negative patients with cryptococcal disease were enrolled. The observation group consisted of patients with disseminated cryptococcosis (DC), whereas the control groups included patients with pulmonary cryptococcosis (PC) and cryptococcal meningitis (CM). Univariate and multivariate logistic regression algorithms were used to explore the significant clinical and laboratory characteristics that affect the progression of cryptococcal infections. Finally, receiver operating characteristics (ROC) curves are applied to assess the diagnostic value of identified risk factors.LE: Kindly check the edit made in the title.I agreeResultsOf the 106 patients, 57 were diagnosed with pulmonary cryptococcosis, 22 with cryptococcal meningitis, and 27 with disseminated cryptococcosis. The logistic regression equation included five variables: diabetes, decompensated liver cirrhosis, long-term use of immunosuppressive agents, decreased serum albumin level, and elevated plasma cytokine IL-10 level. The ROC curves showed that albumin (AUC > 0.7), IL-10 (AUC > 0.7) and decompensated liver cirrhosis (AUC > 0.6) have relatively high diagnostic capacity in predicting the progression of Cryptococcus.ConclusionThis study identified elevated IL-10 levels as an independent risk factor for developing disseminated cryptococcosis in the control groups. Furthermore, decompensated liver cirrhosis and decreased serum albumin independently affected the progression of cryptococcosis in the CM and PC groups, respectively.

Multiple-Factor Analysis of Human Herpes Virus 6 Infection in Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood

Background: Hematopoietic stem cell transplantation (HSCT) can ultimately cure various hematological disorders. Building upon the basis of post-transplant cyclophosphamide (PT-cy) haploidentical HSCT, we innovatively employed a combination of haploidentical related donors and unrelated cord blood donors for complementary transplantation to treat pediatric leukemia and severe thalassemia. This approach has been successful, and complementary transplantation has become an important option in haploidentical HSCT. However, with the development of haploidentical HSCT and the long-term use of immunosuppressive agents, viral infections have gained increasing attention, and human herpesvirus 6 (HHV-6) is one of the concerning viruses. HHV-6 exists in two variants, HHV-6A and HHV-6B, with HHV-6B being the common infection in HSCT. HHV-6B is characterized by a preference for lymphocytes and neurons and can easily reactivate in patients with compromised immune systems after HSCT, leading to severe and irreversible brain and nerve damage, and in severe cases, death. In this study, we aim to identify the susceptible factors for HHV-6B infection in cases of complementary transplantation, with the goal of improving the safety of complementary transplantation in HSCT. Objective: Through a retrospective analysis, we aim to identify the factors associated with HHV-6 infection after complementary transplantation in HSCT, providing clinical evidence for prevention, diagnosis, and treatment. Methods: We selected cases of HSCT using complementary transplantation from December 2018 to May 2022. Factors such as the primary disease of the patients, gender, age, donor-recipient blood type, haploidentical donor engraftment, different HLA-matched cord blood engraftment, neutrophil and platelet engraftment times, use of ATG and glucocorticoids, fever condition, timing of HHV-6 infection, and the time to seronegativity after treatment were analyzed to identify the characteristics and related risk factors of HHV-6B infection. Results: Among 142 cases (73 with thalassemia, 19 with AML, 37 with JMML, 2 with Fanconi anemia, 8 with SAA, and 8 with ALL) using complementary transplantation, 91 cases were infected with HHV-6, resulting in an infection rate of 64%. In the infection group, 8 patients were under the age of 2 years (8.8%), while 83 patients were 2 years or older (91.2%). In the uninfected group, 17 patients were under 2 years of age (33.3%), and 34 patients were 2 years or older (66.7%). (p<0.001). Regarding the type of graft, 79 patients in the infection group received cord blood transplantation (86.8%), and 12 patients received peripheral blood transplantation (13.2%). In the uninfected group, 19 patients received cord blood transplantation (37.3%), and 32 patients received peripheral blood transplantation (62.7%). (p<0.05). Regarding ATG use, 61 patients in the infection group received ATG (67%), and 12 patients did not (33%). In the uninfected group, 25 patients received ATG (49%), and 26 patients did not (51%). (p=0.035). In terms of glucocorticoid use, 82 patients in the infection group received glucocorticoids (90.1%), and 9 patients did not (9.9%). In the uninfected group, 13 patients did not receive glucocorticoids (25.5%), and 38 patients did (74.5%). (p<0.05). Regarding neutrophil engraftment time, it was 36 days in the infection group and 23 days in the uninfected group. Regarding platelet engraftment time, it was 43.5 days in the infection group and 18.5 days in the uninfected group. In terms of CMV and EB virus infection, only one patient in the infection group had concurrent CMV infection, and there were no cases of concurrent EB virus infection. Conclusion: In complementary transplantation, cord blood transplantation, glucocorticoid use, ATG use, and recipient age are high-risk factors for HHV-6 infection/reactivation. There were no significant differences in HHV-6 infection between different diseases treated with complementary transplantation. Furthermore, HHV-6 infection significantly delays the engraftment of neutrophils and platelets. Keywords: Hematopoietic stem cell transplantation, haploidentical, cord blood, human herpesvirus 6 (HHV-6)

Long-Term Use of Immunosuppressive Agents Increased the Risk of Fractures in Patients with Autoimmune Diseases: An 18-Year Population-Based Cohort Study.

The risk of fractures is higher in patients with autoimmune diseases, but it is not clear whether the use of immunosuppressive agents can further increase this risk. To investigate this issue, a retrospective study was conducted using data from Taiwan's National Health Insurance Research Database. Patients diagnosed with autoimmune diseases between 2000 and 2014, including psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, were included in the study. A control group of patients without autoimmune diseases was selected from the same database during the same period. Patients with autoimmune diseases were divided into two sub-cohorts based on their use of immunosuppressive agents. This study found the risk of fractures was 1.14 times higher in patients with autoimmune diseases than in those without. Moreover, we found that patients in the immunosuppressant sub-cohort had a higher risk of fractures compared to those in the non-immunosuppressant sub-cohort. The adjusted sub-distribution hazard ratio for shoulder fractures was 1.27 (95% CI = 1.01-1.58), for spine fractures was 1.43 (95% CI = 1.26-1.62), for wrist fractures was 0.95 (95% CI = 0.75-1.22), and for hip fractures was 1.67 (95% CI = 1.38-2.03). In conclusion, the long-term use of immunosuppressive agents in patients with autoimmune diseases may increase the risk of fractures.

The Synergistic Effect of Full-Spectrum Light Therapy and Transient Immunosuppressants Prolonged Allotransplant Survival.

The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model. Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis. The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) ( P < 0.01). Group 4 also showed a significant increase in regulatory T cells ( P = 0.04) and transforming growth factor-β1 levels ( P = 0.02), and a trend toward a decrease in interleukin-1β levels ( P = 0.03) at 16 weeks after transplantation as compared with control (group 1). FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival. Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival.

The factors predicting development of serious infections in ANCA-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare autoimmune disease usually involving small vessels and progressing with necrotizing inflammation. Treatment requires long-term use of immunosuppressive agents to inhibit disease activity. Serious infections (SIs) are a common complication in AAV. The aim of this study was to identify the risk factors for serious infections which required hospitalization in patients with AAV. In this retrospective cohort study., we included 84 patients admitted to the Ankara University Faculty of Medicine in the last 10 years with a diagnosis of AAV. In 42 (50%) of 84 patients followed up with the diagnosis of AAV, an infection requiring hospitalization was identified. The patients' total corticosteroid dose, use of pulse steroids, induction regimen, levels of C-reactive protein (CRP) and the presence of pulmonary and renopulmonary involvement were found to be associated with the frequency of infection (p=0.015, p=0.016, p=0.010, p=0.03, p= 0.026 and p=0.029, respectively). In multivariable analysis, it was found that renopulmonary involvement (p=0.002, HR=4.95, 95% CI= 1.804-13.605), age of over 65 (p=0.049, HR=3.37, 95% CI=1.004-11.369) and high CRP levels (p=0.043, HR=1.006, 95% CI=1.000-1.011) constituted independent predictors of serious infection risk. The frequency of infection is known to be increased in ANCA-associated vasculitis. Our study showed that renopulmonary involvement, age and elevated CRP levels on admission are independent risk factors of infection.

545. A Retrospective Review of 30-day Mortalities in Solid-Organ Transplant Recipients (SOT) versus Non-Transplant Patients (NTP) Receiving Remdesivir (REM) and Dexamethasone (DEX) for COVID-19 Pneumonia

BackgroundTreating COVID-19 infection in SOT is challenging due to long-term use of immunosuppressive agents. REM is the only FDA-approved anti-viral for SARS-COV-2 infection. DEX showed decrease in mortality in the Recovery Trial. COVID-19 treatment guidelines for SOT patients are the same as NTP despite limited literature on those outcomes. Our primary objective was to determine if 30-day mortality was different between SOT and NTP matched cohorts using these 2 drugs. The secondary objectives included comparisons of length of stay (LOS), days on mechanical ventilation (DMV), and the use of other treatment modalities.MethodsWe retrospectively collected data for hospitalized SOT and NTP, 18 years and older, with pcr-confirmed SARS-CoV-2 infection receiving REM and DEX from May 1, 2020, to October 10, 2020, at Mayo Clinic Florida. IRB approval was obtained. Descriptive statistics were used to analyze the data. Continuous variables were summarized as mean (standard deviation) or median (range) where appropriate, while categorical variables were reported as frequency (percentage).ResultsOf 80 patients who met the inclusion criteria, 28 were SOT, and 52 were NTP. The SOT cohort was subcategorized below:CharacteristicsNumber of SOT (n = 28)Transplant TypeKidney n (%)15 (53.7)Lung n (%)3 (10.7)Liver n (%)2 (7.1)Heart n (%)6 (21.4)Multi-organ n (%)2 (7.1)SOT patients were significantly younger than NTP (p < .001). Further, SOT patients had significantly longer LOS (p = 0.043) and more COVID-19 modalities (75% vs. 36.5%, p = 0.002) compared to NTP. Among the 28 SOT patients, 2 of them died within 30 days of admission, and among the 52 NTP patients, 7 of them died within 30 days. The 30-d survival estimate for SOT group is 92.9% (95% CI: 83.8% - 100.0%) and for NTP group is 86.5% (95% CI: 77.7% - 96.3%). The log-rank test was not significant between the groups (p=0.37), but the NTP has a worse survival curve from the figure below.SOT-NTP Survival Curve ConclusionSOT group was younger, had longer LOS, and more COVID-related modalities. The 30-d survival estimate for SOT group is 92.9% and for NTP group is 86.5%, but the survival curve for NTP was worse likely secondary to age. Use of REM & DEX in SOT recipients is a valid recommendation.Disclosures Claudia R. Libertin, MD, Gilead (Grant/Research Support)

Comparison of FOXP3 and Interleukin 35 Expression Profiles in Kidney Transplant Recipients With Excellent Long-Term Graft Function and Acute Rejection

Transplant tolerance is defined as graft acceptance without long-term use of immunosuppressive agents. Regulatory T cells are involved in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of autoreactive T cells. In the present study, we compared the expression profiles of forkhead box protein P3 (FOXP3) and interleukin 35 in kidney transplant recipients who had excellent long-term graft function under immunosuppression versus recipients who had acute rejection. The 40 kidney transplant recipients included in this study were divided into 2 groups: 27 recipients with excellent long-term graft function and 13 recipients with acute rejection. After collection of whole peripheral blood, peripheral blood mononuclear cells were isolated from the blood samples. After RNAextraction and cDNAsynthesis from each collected sample, expression levels of interleukin 35 and FOXP3 were determined using in-house SYBER green-based real-time polymerase chain reaction. We used t tests to analyze data. Mean ages of recipients with excellent longterm graft function and recipients with acute rejection were 42.1 and 45.5 years, respectively. We found that FOXP3 and interleukin 35 expression levels were significantly increased in recipients with excellentlongterm graftfunction comparedwith recipientswith acute rejection. FOXP3 expression levels were significantly higher in those with excellent long-term graft function with graft survivalrate of <10 years,whereas interleukin 35 expression levels were significantly higher in patients with graft survival rate >10 years (P < .05). Expression levels of FOXP3 and interleukin 35 were greater in those from 35 to 50 years old versus with those in the other age ranges. Expression patterns of FOXP3 and interleukin 35 may have the potential to be used as prognostic biomarkers for kidney transplant outcomes.

Сlinical features of malignant tumors against the background of immunosuppressive therapy in heart transplant recipients

As the survival rate of cardiac recipients improves, higher incidence of malignancy in the late postoperative period becomes essential for their prognosis. Immunosuppressive therapy is one of the key prerequisites for successful transplantation. However, long-term use of immunosuppressive agents increases the incidence of malignant tumors compared to the general population. The risk of their development after organ transplantation increases by 2–4 times compared to the general population. For patients who have undergone transplantation since 2000, the risk of developing malignant neoplasms 1–5 years after surgery is estimated at 10–12%. Timely comprehensive examination of patients, development of new immunosuppression schemes, treatment of those predisposing to the development of malignant neoplasms and giving up harmful habits will reduce the risk of malignant tumors and help diagnose these serious complications at an early stage, which, in turn, will increase the life expectancy of solid organ (particularly the heart) recipients.

Target-oriented delivery of self-assembled immunosuppressant cocktails prolongs allogeneic orthotopic liver transplant survival

Organ transplantation remains the gold standard therapeutic option for patients with end-stage organ failure. However, there have been few improvements in the management of post-transplant immunosuppression. As the long-term use of immunosuppressive agents (ISAs) may result in off-target systemic toxicity and complications, minimizing the ISA dosage while preserving the pharmacological efficacy could be a promising solution to address these challenges. Here, we present the design and application of self-assembled prodrug nanoparticles based on chemically derived mycophenolate mofetil, which further provide a hydrophobic core to noncovalently encapsulate additional ISAs such as tacrolimus. The resulting immunosuppressant cocktail nanoparticles are further refined by PEGylation with amphiphilic polymers to form colloidally stable self-assembled immunosuppressant cocktails (SAICs) that are suitable for preclinical studies. In a rat model of allogeneic orthotopic liver transplantation (OLT), administration of SAICs markedly extends graft/recipient survival, retards weight loss and attenuates allograft damage. Furthermore, SAICs significantly abolish intragraft inflammatory cell infiltration and proinflammatory cytokine profiles as well as improve liver graft function. This study demonstrates the superiority of SAICs over traditional ISAs in the treatment of allograft rejection and may support the emerging application of the SAIC platform in clinical settings.

Insulin-Producing Cell Transplantation Platform for Veterinary Practice.

Diabetes mellitus (DM) remains a global concern in both human and veterinary medicine. Type I DM requires prolonged and consistent exogenous insulin administration to address hyperglycemia, which can increase the risk of diabetes complications such as retinopathy, nephropathy, neuropathy, and heart disorders. Cell-based therapies have been successful in human medicine using the Edmonton protocol. These therapies help maintain the production of endogenous insulin and stabilize blood glucose levels and may possibly be adapted to veterinary clinical practice. The limited number of cadaveric pancreas donors and the long-term use of immunosuppressive agents are the main obstacles for this protocol. Over the past decade, the development of potential therapies for DM has mainly focused on the generation of effective insulin-producing cells (IPCs) from various sources of stem cells that can be transplanted into the body. Another successful application of stem cells in type I DM therapies is transplanting generated IPCs. Encapsulation can be an alternative strategy to protect IPCs from rejection by the body due to their immunoisolation properties. This review summarizes current concepts of IPCs and encapsulation technology for veterinary clinical application and proposes a potential stem-cell-based platform for veterinary diabetic regenerative therapy.

Primary Cutaneous Aspergillosis Presenting as a Multiloculated Cyst in the Hand

: Invasive aspergillosis typically occurs in immunocompromised patients and results in fatal complications. Musculoskeletal involvement of aspergillosis is extremely rare, therefore, when it occurs, its diagnosis and treatment could be delayed. In this paper, we report a rare case of primary invasive aspergillosis with radiologic findings in a patient with rheumatoid arthritis. A 57-year-old woman presented a palpable mass on the right hand with a previous medical history of long-term use of immunosuppressive agents due to rheumatoid arthritis. Magnetic resonance imaging showed a multilobulated and multiloculated cystic lesion with an enhancing wall. The wall of the cystic lesion showed low signal intensity on T2 weighted images and intermediate to high signal intensity on T1 weighted images. The mass was confirmed as chronic granulomatous inflammation with multiple acute branching and septated fungal hyphae, consistent with invasive aspergillosis. When a superficial multicystic mass in the hand of especially immunocompromised patients is encountered, invasive aspergillosis should be included in the differential diagnosis, although it is rare.

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Evidence‐based consensus on opportunistic infections in inflammatory bowel disease

Progress and prospect of treatment for ocular Behçet disease

Ocular Behcet disease, which usually presents as panuveitis, with characteristic of vision impairment and relapse, is one of the most refractory uveitis entities.Usually, one or more conventional immunosuppressive agents, such as glucocorticoid, ciclosporin, chlorambucil, cyclophosphamide, etc, are needed in disease management.However, long-term use of immunosuppressive agents would result in severe adverse effects.New biologics, such as interferon, antitumor necrosis factor agents, interleukin or its receptor antagonists, provide new therapeutic approaches to the treatment for this disease.This paper reviewed the conventional therapies and biologics applied in ocular Behcet disease. Key words: Behcet disease, Uveitis; Treatment; Immunosuppressive agent; Biologics

Decrease of Functional Activated T and B Cells and Treatment of Glomerulonephitis in Lupus-Prone Mice Using a Natural Flavonoid Astilbin.

Treatment of systemic lupus erythematosus (SLE), a chronic inflammatory disease, involves the long-term use of immunosuppressive agents with significant side effects. New therapeutic approaches are being explored to find better treatment possibilities. In this study, age-matched female MRL/lpr mice were treated orally with a natural flavonoid astilbin. Astilbin administration started either at week 8 or week 12 of age though week 20. In the early treatment regimen, the treatment with astilbin reduced splenomegaly / lymphomegaly, autoantibody production and ameliorated lupus nephitis. Several serum cytokines were significantly decreased upon treatment including IFN-g, IL-17A, IL-1b, TNF-a and IL-6. Both spleen CD44hiCD62Llo activated T cells and CD138+B220- plasma cells greatly declined. Furthermore, astilbin treatment resulted in decreased mitochondrial membrane potential in activated T cells and downregulated expression of the co-stimulatory molecules CD80 and CD86 on LPS stimulated B cells. Similar but less profound effectiveness was observed in the mice with established disease in the late treatment regimen. These results indicate that the natural product astilbin can mitigate disease development in lupus-prone mice by decreasing functional activated T and B cells.

Ideal vaccination strategy in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a long-standing disease that often requires long-term use of immunosuppressive agents including immunomodulators (such as azathioprine, 6-mercaptopurine and methotrexate) and tumor necrosis factor-α inhibitors (such as infliximab and adalimumab). Introduction of immunosuppressive therapies, however, involves the risk of host susceptibility to opportunistic infections in this patient population. Therefore, adequate immunization for vaccine-preventable infectious diseases is currently recommended for all patients with IBD and is emerging as an important target for quality improvements in IBD care. However, ongoing issues regarding underuse of immunization, safety and efficacy of vaccines in patients with IBD remain. For quality improvements in IBD care, all physicians should follow the recent immunization guidelines proposed by professional IBD societies. Additionally, there are ongoing needs for intensive educational programs regarding a role of immunization in long-term care of IBD and up-to-date immunization guidelines. Immunization status should be checked at the time of diagnosis of IBD and timely vaccination before initiation of immunosuppressive therapies can be a practical solution for maximizing the efficacy of vaccination at this point. Inactivated vaccines can be used safely irrespective of immunization status of patients, while attenuated vaccines are contraindicated in patients on immunosuppressive therapies. This article reviews an ideal strategy for vaccinating patients with IBD based on the currently recommended immunization guidelines.

Clinical transplantation tolerance

Transplantation is the treatment of choice for many if not most causes of end-stage organ failure. Over 20,000 organ transplant procedures were performed in the USA in 2009 to treat patients with failed or failing kidneys, livers, hearts, lungs, and intestines, and there remain 85,000 individuals waiting on the transplant list. Currently, in the USA, there are over 170,000 individuals living with a transplanted organ. Virtually, all of these individuals receive maintenance immunosuppression in an attempt to maximize the function and survival of the transplanted organ. However, it is clear that the long-term use of immunosuppressive agents is associated with an extensive list of undesirable side effects that have the potential to limit the survival of the patient and transplanted organ as well as to compromise quality of life. Although the ability to induce reproducibly a state of robust, stable tolerance would address this problem, tolerance remains an infrequent event in clinical transplantation that is largely a consequence of chance. Factors limiting the broader investigation of clinical transplantation tolerance include the lack of therapeutic regimens known to favor tolerance in humans, the lack of validated assays or biomarkers predictive of tolerance, and concerns about the safety and ethics of complete withdrawal of immunosuppression given the very good results achievable with current immunosuppression. Despite these barriers, a number of investigators have continued to conduct well-designed and carefully supervised studies with the long-term goal of making clinical transplantation tolerance more feasible. The aim of this review is to summarize the status of these studies.

Association Between Cancer and Immunosuppressive Therapy—Analysis of Selected Studies in Pemphigus and Pemphigoid

To determine whether there is an association between the use of immunosuppressive agents (ISAs) and cancer in patients with pemphigus and pemphigoid-rare, potentially fatal diseases of the skin and mucous membranes, often requiring long-term use of ISAs. Literature was accessed through PubMed (all years available), using the search terms cancer, immunosuppressive agents, pemphigoid, and pemphigus. A retrospective review of the literature was conducted. Inclusion criteria for studies were: (1) English language, (2) diagnosis of pemphigus and/or pemphigoid based on histology and immunopathology, (3) more than 10 patients evaluated, (4) investigators had a high index of suspicion of cancer and patients were monitored for it, (5) follow-up information was provided for at least 1 year after initiation of therapy, and (6) absence of diagnosis of cancer before initiation of an ISA. Case reports were not included in the analysis. A total of 929 patients diagnosed with either pemphigus or pemphigoid in 17 studies were identified. Patients were divided into 2 groups. Group A comprised patients treated with azathioprine, cyclophosphamide, cyclosporine, or mycophenolate mofetil in combination with prednisone. In Group A, 22 cases of cancer were reported in 21 of the 218 patients (9.6%). Group B comprised patients treated with systemic corticosteroids only. In this group, cancer was reported in 11 of the 711 patients (1.5%). In this study there was no control group (untreated patients) and the sample sizes were small. Preliminary data suggest a possible association between the use of azathioprine, cyclophosphamide, and cyclosporine and increased susceptibility to cancer in patients with pemphigus and pemphigoid.

Efficacy and safety of long‐term mycophenolate sodium therapy in pemphigus vulgaris

Pemphigus is a chronic immunobullous disease, characterized by formation of blisters and erosions in skin and/or mucous membranes. This severe disease requires systemic immunosuppressive therapy. However, some patients are refractory, and long-term use of immunosuppressive agents can cause serious side-effects. Mycophenolic acid is increasingly being used as a corticosteroid-sparing agent or as monotherapy in immunosuppressive regimens. We aimed to evaluate the effectiveness of mycophenolate sodium, a sodium salt of mycophenolic acid, in the treatment of pemphigus vulgaris. Six patients who were diagnosed as pemphigus vulgaris with active, refractory disease were treated with mycophenolate sodium. Three patients received mycophenolate sodium monotherapy; three patients received mycophenolate in combination with steroid. All patients were monitored regularly. Mycophenolate sodium was well tolerated with a similar efficacy of mycophenolate mofetil, and no side-effects have been observed. Mycophenolate sodium appears to be an effective and safe alternative in the treatment of pemphigus vulgaris.

Statins induce immunosuppressive effect on heterotopic limb allografts in rat through inhibiting T cell activation and proliferation

Long-term use of immunosuppressive agents could bring many side effects. Recently, 3-Hydroxy-3-methyl-gutaryl coenzyme A reductase inhibitors (statins) have been reported to be immunomodulatory besides lowering serum cholesterol level. The aim of this study was to investigate the effects of statins on composite tissue allografts and T lymphocyte in vivo and in vitro. Rats were divided into 5 groups: syngeneic transplantation group (Lewis–Lewis); allogeneic control group (Brown Norway–Lewis, no treatment); low-dose statins group (15 mg /kg); high-dose statins group (30 mg /kg) and cyclosporin A group. In vivo, treatment of statins significantly prolonged allografts survival as compared to control group. Histological findings further supported these clinical results and demonstrated less extent of rejection. Immunohistochemical analysis showed that there was a remarkably reduced T cells infiltration in statins groups. Moreover, the serum levels of IL-2 and IFN-γ were decreased after statins therapy, while these in control group increased significantly. Meanwhile, transcriptional activities of IL-2 and IFN-γ were also dramatically down-regulated after statins treatment. In vitro, mixed lymphocyte reaction assay was performed and the results revealed lymphocyte proliferation was inhibited by statins in a dose-dependent manner. Furthermore, administration of statins exhibited inhibitory effects on CD3/CD28 mediated T cell activation and proliferation. Besides, the results demonstrated that statins significantly down-regulated mRNA expression and suppress cytokine production of IL-2 and IFN-γ in vitro. In conclusion, our data demonstrated that application of statins could induce immunosuppressive effect and prolong allografts survival through inhibiting activation and proliferation of T cell and reducing production of IL-2 and IFN-γ.

Donor-specific tolerance induction in composite tissue allografts

BACKGROUND: Although prolonged composite tissue allograft (CTA) survival is achievable in animals using immunosuppressive drugs, long-term immunosuppression of CTAs in the clinical setting would be unacceptable for most patients. The purpose of this study was to develop a model for reliable CTA tolerance induction in the adult rat across a strongly antigenic MHC mismatch without the need for long-term immunosuppression. METHODS: Chimeras were prepared using rat strains with strong MHC incompatibility [WF (RT1A u) + ACI (RT1A a) → WF, n = 13]. Syngeneic (WF) and allogeneic (ACI) bone marrow (BM) was harvested and T-cell depleted. Following confirmation of T-cell depletion by flow cytometry, a mixture of T-cell depleted syngeneic and allogeneic BM was injected into the recipient animals (all recipients pretreated with low-dose irradiation, 500 to 700 cGy). In addition, the recipient animals received a single dose of ALS (10 mg) 5 days prior to bone marrow transplantation (BMT) and tacrolimus (1 mg/kg/day) from the day prior to BMT to 10 days postoperatively. Rat chimeras were characterized by flow cytometry at 3 and 12 months after BM reconstitution and following hindlimb transplantation. RESULTS: Peripheral blood lymphocyte chimerism (WF/ACI) remained stable >12 months after BM reconstitution in 10 of 13 animals. Multilineage chimerism of both lymphoid and myeloid lineages was present, suggesting that engraftment of the pluripotent rat stem cell had occurred. In animals with donor chimerism >60%, there was no sign of limb rejection for the duration of the study. All animals with chimerism <20% developed moderate signs of rejection clinically and histologically. Gross motor and sensory reinnervation (weight bearing, toe spread) occurred at >60 days in 6 of 9 rats. Postoperative flow cytometry studies demonstrated stable chimerism in all animals studied (n = 7). CONCLUSIONS: Stable mixed allogeneic chimerism can be achieved in a rat hindlimb model of composite tissue allotransplantation. Hindlimb allografts to mixed allogeneic chimeras exhibit prolonged, rejection-free survival. This represents the first reliable model demonstrating rejection-free CTA survival in an adult animal without the long-term use of immunosuppressive agents across a strongly antigenic MHC mismatch.