Exacerbation Of Autoimmune Diseases Research Articles

New perspective on the treatment of rheumatic arthritis based on “strengthening body resistance (Fú Zhèng)” in the theory of co-inhibitory receptor-regulated T-cell immunity

Co-inhibitory receptors serve as crucial regulators of T-cell function, playing a pivotal role in modulating the delicate balance between immune tolerance and autoimmunity. Initially identified in autoimmune disease models, co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, and TIGIT, were found to be integral to immune regulation. Their blockade or absence in these models resulted in the induction or exacerbation of autoimmune diseases. Additionally, scholars have observed that co-inhibitory receptors on lymphocytes hold the potential to influence the prognosis in the context of chronic inflammation. Consequently, the blocking of co-suppressor receptors has emerged as a novel therapeutic approach for inhibiting refractory inflammatory diseases, particularly rheumatoid arthritis. From the standpoint of traditional Chinese medicine (TCM), the treatment of rheumatoid arthritis based on the “strengthening body resistance (Fú Zhèng)” theory can be construed as the regulation of co-suppressor receptors to modulate the body’s immune function in combating chronic inflammation. This article provides a succinct overview of the role of co-suppressor receptors in anti-inflammatory processes and explores the research prospects of co-suppressor receptor intervention in the treatment of rheumatoid arthritis. The exploration integrates the “strengthening body resistance (Fú Zhèng)” theory with relevant Chinese medicine formulations.

Assessing the Impact of Influenza Vaccination Timing on Experimental Arthritis: Effects on Disease Progression and Inflammatory Biomarkers.

Numerous studies have indicated a link between vaccines and the exacerbation of autoimmune diseases including rheumatoid arthritis (RA). However, there is no consensus in clinical practice regarding the optimal timing of immunization. Therefore, this study aimed to investigate the impact of the 3Fluart influenza vaccine on the complete Freund's adjuvant (CFA)-induced chronic arthritis rat model and to identify new biomarkers with clinical utility. CFA was injected into the plantar surface of one hind paw and the root of the tail on day 0, and the tail root injection was repeated on day 1. Flu vaccination was performed on day 1 or 7. Paw volume was measured by plethysmometry, mechanonociceptive threshold by dynamic plantar aesthesiometry, neutrophil myeloperoxidase (MPO) activity, and vascular leakage using in vivo optical imaging throughout the 21-day experiment. Inflammatory markers were determined by Western blot and histopathology. CFA-induced swelling, an increase in MPO activity, plasma extravasation in the tibiotarsal joint. Mechanical hyperalgesia of the hind paw was observed 3 days after the injection, which gradually decreased. Co-administration of the flu vaccine on day 7 but not on day 1 resulted in significantly increased heme oxygenase 1 (HO-1) expression. The influenza vaccination appears to have a limited impact on the progression and severity of the inflammatory response and associated pain. Nevertheless, delayed vaccination could alter the disease activity, as indicated by the findings from assessments of edema and inflammatory biomarkers. HO-1 may serve as a potential marker for the severity of inflammation, particularly in the case of delayed vaccination. However, further investigation is needed to fully understand the regulation and role of HO-1, a task that falls outside the scope of the current study.

A Comprehensive Review of 16 Existing Reviews that Investigate the Influence of Stress on the Onset and Exacerbation of Autoimmune Diseases

A Comprehensive Review of 16 Existing Reviews that Investigate the Influence of Stress on the Onset and Exacerbation of Autoimmune Diseases

Newly diagnosed ANCA-associated vasculitis after COVID-19 infection: a case report

BackgroundAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by mononuclear cell infiltration and small and medium-sized blood vessel destruction leading to renal failure. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to have the potential to induce the presentation or exacerbation of autoimmune disease. This report describes the clinical features of a case of newly diagnosed ANCA-associated vasculitis after COVID-19 Infection.Case presentationDuring the COVID-19 pandemic, a 67- year-old female Japanese was undergoing treatment for interstitial pneumonia, diabetes mellitus, and hypertension at her local doctor. About 2 months ago, she was diagnosed with COVID-19 and went to a hotel for treatment, and her condition improved. But a month later, after her COVID-19 infection, she presented with a fever and cough and visited Yodogawa Christian Hospital in Osaka, Japan. The reverse transcription-polymerase chain reaction was negative. She underwent extensive radiological and laboratory investigations. Serologies revealed a high perinuclear-ANCA titer with a specific anti-myeloperoxidase antibody titer of 31.7 units/mL. We suspected ANCA-associated vasculitis and performed a renal biopsy. Renal biopsy showed evidence of crescentic glomerulonephritis, which was consistent with ANCA-associated vasculitis. The patient was referred to the Department of Rheumatology and Clinical Immunology for steroid pulse and cyclophosphamide treatment.ConclusionsDelayed screening may lead to progression of the autoimmune disease, so prompt diagnosis is necessary. In this case, we could make an immediate diagnosis and refer the patient to the Department of Rheumatology and Clinical Immunology.

Impact of SARS-CoV-2 mRNA vaccine on arthritis condition in rheumatoid arthritis.

The SARS-CoV-2 mRNA vaccine has been reported to cause various adverse reactions, including the development or exacerbation of autoimmune diseases, but the adverse reactions and the effects of the vaccines on disease activity in patients with rheumatoid arthritis (RA) remain unknown. We therefore investigated the arthritis condition in RA patients after SARS-CoV-2 vaccination. RA patients who visited our hospital from January to April 2022 completed a questionnaire regarding adverse reactions to the SARS-CoV-2 vaccine. We compared the frequency and duration of post-vaccination arthralgia between RA patients and health care workers in our hospital. For the RA patients who reported post-vaccination arthralgia, we collected medical records for the 6 months after vaccination. Of the 1198 vaccinated RA patients, 256 (21.4%) had systemic inflammatory symptoms, 18 (1.5%) had allergies including urticaria and asthma, and 37 (3.1%) had arthralgia. A few patients had extra-articular manifestations such as acute exacerbation of interstitial lung disease. Compared with health care workers, RA patients more frequently developed arthralgia, and the arthralgia was longer lasting than that in controls: only 9 (0.8%) of the 1117 health care workers reported arthralgia, and all cases resolved within 3 days. Data from 31 of the 37 RA patients with post-vaccination arthralgia were further analyzed; in these patients, disease activity was highest after 2 months, and 10 patients required additional DMARDs within 6 months. The proportion of concomitant use of PSL at vaccination was higher in these patients. No patients on biological DMARDs or targeted synthetic DMARDs prior to vaccination needed additional DMARDs or a change of regimen. RA patients had more frequent and longer-lasting arthralgia after vaccination than healthy subjects, and one-third of patients with post-vaccination arthralgia required additional DMARDs. Although the SARS-CoV-2 mRNA vaccine was administered safely in most RA patients, in some patients RA symptoms may worsen after vaccination.

Primena nivolumaba kod bolesnice sa mukozalnim melanomom i sistemskim lupusom - prikaz slučaja sa pregledom literature

Introduction. Systemic lupus erythematosus (SLE) represents a multisystemic disease characterized by antibody production, complement activation, and immune complexes deposition. Certain types of malignancies occur more often, and conversely, some of them occur less often in SLE patients. Mucosal melanoma of the anorectal region represents a rare form of melanoma occurring in 1.5% of all melanoma patients, predominantly female. The introduction of novel agents dramatically changed the outcome in melanoma patients and introduced different adverse events, diverse contraindications, and drug interactions. Immune checkpoint inhibitors have a role in the maintenance of immunologic homeostasis. Patients with underlying autoimmune diseases were often excluded from clinical trials, for fear of possible autoimmune disease exacerbation or high-grade immune-related adverse events. Due to that, data regarding this subgroup of patients is limited, with no clear recommendations. Given the fact that prevalence among the general population is high (5-10%), autoimmune diseases represent common comorbidity in cancer patients. Having that in mind, it is of utmost importance to personalize the approach and individualize the SLE treatment and enable the use of PD-1 antibody in the safest and most useful way while keeping the SLE in control. Case report. Herein we present a 79-year-old with primary mucosal melanoma of the anorectal region, with lung metastasis and preexisting SLE in remission. Hydroxychloroquine was the only treatment for SLE. Nivolumab treatment was initiated in the standard dosing schedule. After the first and second follow-up, no further progression of melanoma was detected, with no SLE exacerbation and immune-related adverse events. Conclusion. PD-1 treatment in a patient with an underlying autoimmune disease represents a viable choice with a necessity for a multidisciplinary approach and close monitoring.

C-ANCA-associated vasculitis with predominant CNS demyelination after COVID-19

COVID-19 infection may trigger the presentation or exacerbation of autoimmune diseases. c-Antineutrophil cytoplasmic antibody (c-ANCA)-associated vasculitis after COVID-19 mainly involves the kidneys and lungs, and is rarely reported. We describe the case of a 13-year-old girl with a history of chronic immunologic thrombocytopenic purpura who presented with transverse myelitis and central nervous system demyelination, and was subsequently diagnosed with c-ANCA-associated vasculitis following COVID-19. The patient's condition improved after pulse therapy with methylprednisolone and rituximab. To our knowledge, this is the first reported pediatric case of ANCA-associated vasculitis with predominant central nervous system involvement after COVID-19 infection.

Transcriptomics and quantitative proteomics reveal changes after second stimulation of bone marrow-derived macrophages from lupus-prone MRL/lpr mice.

Innate immune memory can cause the occurrence and exacerbation of autoimmune diseases, and it is as well as being strongly associated with the pathogenesis of systemic lupus erythematosus (SLE), however, the specific mechanism remains to be further studied. We learned that IFN-γ stimulation generated innate immune memory in bone marrow-derived macrophages (BMDMs) and activated memory interferon-stimulated genes (ISGs). This research used IFN-γ and lipopolysaccharide (LPS) to treat BMDMs with lupus-prone MRL/lpr mice and showed that particular memory ISGs were substantially elevated in prestimulated macrophages. In order to identify the differentially expressed genes (DEGs), researchers turned to RNA-seq. GO and KEGG analysis showed that up-regulated DEGs were enriched in defense and innate immune responses, and were related to the expression of pattern recognition receptors (PRRs)-related pathways in macrophages. TMT-based proteome analysis revealed differentially expressed proteins (DEPs) up-regulated in BMDMs were abundant in metabolic pathways such as glucose metabolism. Our study found that after the secondary stimulation of MRL/lpr mice, the expression of PRRs in innate immune cells was changed, and IFN-related pathways were activated to release a large number of ISGs to promote the secondary response. At the same time, related metabolic modes such as glycolysis were enhanced, and epigenetic changes may occur. Therefore, SLE is brought on, maintained, and worsened by a variety of factors that work together to produce innate immune memory.

Worsening of a progressive interstitial lung disease in a patient with adult Still's disease after a novel coronavirus infection

Adult Still's disease is a rare systemic disorder of unknown etiology. Its course is often complicated by interstitial pneumonia and fulminant hepatitis. Published data have indicated some common mechanisms of systemic inflammation in patients with autoimmune disorders and SARS-COV-19. We present a clinical case of a 74-year old female patient with a long standing, slowly progressive Stills disease, who developed honeycomb lung and severe liver injury as major syndromes after a novel coronavirus infection. Within 10 months, she developed increasing dyspnea, progressive fibrous pulmonary abnormalities with formation of a "honeycomb lung" and signs of liver failure. Due to late medical referral, these symptoms have led to the patients death. According to the literature, lung tissue abnormalities that persist after a new coronavirus infection in patients with autoimmune disorders can be both a manifestation of residual post-covid injury and a systemic disease-associated lung injury with COVID-19-triggered progression. By this clinical example, we intended to illustrate that the key to a correct diagnosis is multiple organ damage persisting after a novel coronavirus infection irrespective of the severity of the coronavirus lung injury. Such symptoms indicate the need to assess immunological markers to exclude an autoimmune disease exacerbation or onset. Clinicians should aim at rapid diagnosis and timely initiation of specific therapy.

Gut Microbiota, Leaky Gut, and Autoimmune Diseases.

With the rising prevalence of autoimmune diseases, the role of the environment, specifically the gut microbiota, in disease development has grown to be a major area of study. Recent advances show a relationship and possible cause and effect between the gut microbiota and the initiation or exacerbation of autoimmune diseases. Furthermore, microbial dysbiosis and leaky gut are frequent phenomena in both human autoimmune diseases and the murine autoimmunity models. This review will focus on literature in recent years concerning the gut microbiota and leaky gut in relation to the autoimmune diseases, including systemic lupus erythematosus, type 1 diabetes, and multiple sclerosis.

Effect of polycyclic aromatic hydrocarbons on immunity

Nearly a quarter of the total number of deaths in the world are caused by unhealthy living or working environments. Therefore, we consider it significant to introduce the effect of a widely distributed component of air/water/food-source contaminants, polycyclic aromatic hydrocarbons (PAHs), on the human body, especially on immunity in this review. PAHs are a large class of organic compounds containing two or more benzene rings. PAH exposure could occur in most people through breath, smoke, food, and direct skin contact, resulting in both cellular immunosuppression and humoral immunosuppression. PAHs usually lead to the exacerbation of autoimmune diseases by regulating the balance of T helper cell 17 and regulatory T cells, and promoting type 2 immunity. However, the receptor of PAHs, aryl hydrocarbon receptor (AhR), appears to exhibit duality in the immune response, which seems to explain some seemingly opposite experimental results. In addition, PAH exposure was also able to exacerbate allergic reactions and regulate monocytes to a certain extent. The specific regulation mechanisms of immune system include the assistance of AhR, the activation of the CYP-ROS axis, the recruitment of intracellular calcium, and some epigenetic mechanisms. This review aims to summarize our current understanding on the impact of PAHs in the immune system and some related diseases such as cancer, autoimmune diseases (rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), and allergic diseases (asthma and atopic dermatitis). Finally, we also propose future research directions for the prevention or treatment on environmental induced diseases.

Neutrophil Extracellular Traps (NETs) and Hypercoagulability in Plasma Cell Dyscrasias-Is This Phenomenon Worthy of Exploration?

Plasma cell dyscrasias (PCDs) are neoplastic diseases derived from plasma cells. Patients suffering from PCDs are at high risk of hypercoagulability and thrombosis. These conditions are associated with disease-related factors, patient-related factors, or the use of immunomodulatory drugs. As PCDs belong to neoplastic diseases, some other factors related to the cancer-associated hypercoagulability state in the course of PCDs are also considered. One of the weakest issues studied in PCDs is the procoagulant activity of neutrophil extracellular traps (NETs). NETs are web-like structures released from neutrophils in response to different stimuli. These structures are made of deoxyribonucleic acid (DNA) and bactericidal proteins, such as histones, myeloperoxidase, neutrophil elastase, and over 300 other proteins, which are primarily stored in neutrophil granules. NETs immobilize, inactivate the pathogens, and expose them to specialized cells of immune response. Despite their pivotal role in innate immunity, they contribute to the development and exacerbation of autoimmune diseases, trigger inflammatory response, or even facilitate the formation of cancer metastases. NETs were also found to induce activity of coagulation and are considered one of the most important factors inducing thrombosis. Here, we summarize how PCDs influence the release of NETs, and hypothesize whether NETs contribute to hypercoagulability in PCDs patients.

Ethnicity is a major determinant of the pattern of dermatological diseases among pilgrims during the Hajj in 2019.

The authors aim to explore the pattern and demographics of dermatological disorders occurring during Hajj 2019. Clinical records from three major public healthcare facilities in Al-Madinah Al-Munawara were retrieved for the period July-August, 2019. Collected data included age, gender, nationality, and dermatological complaints. 550 records were retrieved. Patients were 282 (51.3%) males and 268 (48.7%) females with a mean age of 58.3±12.6 years. Most patients were Asians (n=320, 58.2%), and Africans (n=183, 33.3%). Accidents (n=226, 41.1%), and infections (148, 26.9%) were the most common complaints. Asians and Africans had significantly: more accidents and less infections (P=0.002, P=0.027 respectively). They were the only category affected by exacerbations of auto immune diseases. Asian and African pilgrims are mainly affected by traumatic dermatologic conditions. Preventive awareness programs should target these ethnicities to reduce their higher rates of accidents. Other ethnicities need programs that promote hygienic practices and target infections.

Oral manifestations of COVID-19: Brief review

The infection with a new type of virus - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - called coronavirus disease 2019 (COVID-19) was first described in December 2019, in Wuhan, China. Due to the gastrointestinal mucosa tropism of the virus, an attempt was made to describe the oral manifestations of the SARS-CoV-2 infection. Angiotensin-converting enzyme 2 (ACE2), which permits the attachment of the virus, is present also in the oral cavity. There are many symptoms in the oral cavity; among them, the most prevalent ones are dysgeusia (taste disorders), oral pain, the exacerbation of autoimmune diseases as well as the herpes simplex virus (HSV) and varicella zoster virus (VZV) infections. Ulcerations and aphthous stomatitis are also often mentioned. The research shows that there are many oral symptoms in COVID-19, but the coexistence with the main disease has not been fully stated and understood. There is still no clearance on whether the oral symptoms are the manifestations of the disease or occur due to the loss of the immune response. Therefore, further studies on this subject should be conducted.

Pembrolizumab-Induced Myasthenia Gravis in a Patient with Thymic Carcinoma

Pembrolizumab is an immune checkpoint inhibitor. Most cases of myasthenia gravis (MG) reported with the use of immune checkpoint inhibitors have been in melanomas, and small and non-small cell lung carcinoma, but there are no reported cases in thymic epithelial carcinoma. A 57-year-old male with thymic carcinoma presented with symptoms of diplopia, drooping eyelids, and difficulty in talking and swallowing after a second dose of pembrolizumab. Contrast-enhanced brain magnetic resonance imaging, laboratory tests, and electroneuromyography were normal. Single-fiber electromyography showed increased jitter (six muscle fibers were collected, range of jitter 29–140 μs, mean 75 μs; normal <35 μs) in bilateral orbicularis oculi muscles supporting MG. Serum screening showed no any positivity for acetylcholine receptor and muscle-specific tyrosine kinase autoantibodies. The patient died of bulbar dysfunction related to aspiration pneumonia despite receiving intravenous immunoglobulin and methylprednisolone therapy. Physicians should be alert to possible exacerbations of autoimmune diseases and associated risks, especially during treatment with checkpoint inhibitors in thymic malignancy.

Surface Layer Protein A Expressed in Clostridioides difficile DJNS06-36 Possesses an Encephalitogenic Mimotope of Myelin Basic Protein.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Recent studies suggest that migration of Th1 and Th17 cells specific for enteric bacteria from the gut to the CNS may lead to the initiation and/or exacerbation of autoimmune diseases including MS. Human leukocyte antigen (HLA)-DR15 is an MHC class II (MHCII) haplotype highly associated with the development of MS that contains the two HLA-DRB* genes, DRB1*1501 (DR2b) and DRB5*0101 (DR2a). To identify enteric bacteria which harbor antigenic epitopes that activate myelin-specific T cells and drive CNS inflammation, we screened for enteric bacteria which express cross-reactive epitopes (‘mimotopes’) of an immunodominant myelin basic protein 89–98 (MBP89-98) epitope. Based on known MHCII HLA-DR2a amino acid binding motifs and cultivation with splenic T cells isolated from MBP-T cell receptor (TCR)/DR2a transgenic (Tg) mice, we discovered that a certain variant of surface layer protein A (SLPA), which is expressed by a subtype of Clostridioides difficile, contains an amino acid sequence that activates MBP89-98-reactive T cells. Furthermore, activation of MBP-specific T cells by SLPA upon active immunization induced experimental autoimmune encephalomyelitis (EAE) in MBP-TCR/DR2a Tg mice. This study suggests that a unique strain of C. difficile possesses an encephalitogenic mimotope of MBP that activates autoreactive, myelin-specific T cells.

Epstein-Barr Virus Reactivation-Induced Immunoglobulin Production: Significance on Autoimmunity.

Epstein–Barr virus (EBV) mainly persists in B cells, which differentiate into antibody-producing cells, and thus, EBV has been implicated in autoimmune diseases. We aimed to describe the EBV reactivation and its relevance to autoimmune disease, focusing on Graves’ disease, which is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies. Circulating autoreactive B cells that have evaded from the selection have difficulties differentiating to produce antibodies. However, once EBV infects such B cells and reactivates, the B cells may become plasma cells and produce autoantibody. We herein proposed an EBV reactivation-induced Ig production system, which is a distinct pathway from the antibody production system through germinal centers and bone marrow and has the following characteristics: 1. IgM dominance, 2. ubiquitous Ig production, and 3. the rescue of autoreactive B cells, which skews Ig production toward autoantigens. IgM autoantibodies induced by EBV reactivation may activate the classical complement pathway and injure healthy tissue, which supply autoantigens for the production of affinity-matured IgG autoantibodies. Antibodies induced by EBV reactivation may play important roles in the development and exacerbation of autoimmune diseases.

Lung Cancer Immunotherapy in Transplant Patients and in Patients With Autoimmune Diseases.

The use of immune checkpoint inhibitors (ICIs) delivered great and new possibilities in modern treatment of many types of cancers. This therapy based on blockade of such molecules as CTLA-4 (cytotoxic T lymphocyte-associated antigen), PD-1 (programmed cell death receptor type 1), or PD-1 ligand (PD-L1) brings a new hope for patients with non-small cell lung cancer (NSCLC), melanoma, or head and neck squamous carcinoma. Efficacy of immunotherapy was proven in many clinical trials. Unfortunately, ICIs treatment was not addressed to the patients with preexisting allogeneic transplants or autoimmune diseases mainly due to high risk of transplant rejection, exacerbation of autoimmune diseases, and risk of serious toxicity. However, it is possible to receive anti-tumor response to ICIs treatment avoiding graft rejection by adjusting the immunosuppression. Obviously, it depends on the type of transplants: the use of immunotherapy is usually possible in kidney or corneal recipients, but it could be difficult in patients with liver and heart transplant. Therefore, the development of biomarkers for tumor response and transplant rejection in ICIs treated patients is essential. Data coming from published literature support the possibilities of using ICIs in patients with preexisting autoimmune diseases who undergoing proper management of side effects of immunotherapy or when the potential benefits of such treatment outweigh the potential risks. This depends on the type of autoimmune disease and may be difficult or not feasible in patients with systemic lupus erythematosus or systemic sclerosis. Therefore, it may be appropriate to include cancer patients with preexisting autoimmune disease or with allogeneic transplants in clinical trials using immunotherapy when no other effective cancer treatment options exist.

Pharmacologic management of patients with hepatic and pancreatic diseases that involve immunosuppressive therapies. Positioning within the framework of the SARS-CoV-2 (COVID-19) pandemic

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. COVID-19 affected close to 2 million persons worldwide in fewer than 4 months, after the report of the first cases in China in December 2019. The relation of the disease caused by SARS-Cov-2 to immunosuppressive treatment used in different gastrointestinal disorders is uncertain, resulting in debate with regard to suspending immunosuppressive therapy to improve infection outcome. Said suspension implies the inherent risk for graft rejection or autoimmune disease exacerbation that can potentially worsen the course of the infection. Based on the presently available evidence, a treatment stance has been established for patients with gastrointestinal diseases that require immunosuppressive therapy.

Pharmacologic management of patients with hepatic and pancreatic diseases that involve immunosuppressive therapies. Position statement within the framework of the SARS-CoV-2 (COVID-19) pandemic.

ResumenLa enfermedad por coronavirus 2019 (COVID-19) es causada por el virus del síndrome respiratorio agudo grave-coronavirus 2 (SARS-CoV-2). La COVID-19 ha afectado a unos 6 millones de personas en todo el mundo en menos de 4 meses posterior al reporte de los primeros casos en China en diciembre de 2019. La relación que guarda la enfermedad por SARS-CoV-2 con el tratamiento inmunosupresor utilizado en diversos trastornos gastrointestinales es incierta, y esto genera el debate sobre suspender el tratamiento inmunosupresor para mejorar el pronóstico de la infección, lo cual incluye el riesgo inherente de rechazo de injerto o agudización de enfermedades autoinmunes que potencialmente pudieran agravar el curso de la infección. En base a la evidencia disponible se logra establecer una postura de tratamiento en pacientes con enfermedades gastrointestinales que requieren terapia inmunosupresora.