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Systemic lupus erythematosus: pathogenesis and targeted therapy.

Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by dysregulated immune responses and autoantibody production, which affects multiple organs and varies in clinical presentation and disease severity. The development of SLE is intricate, encompassing dysregulation within the immune system, a collapse of immunological tolerance, genetic susceptibilities to the disease, and a variety of environmental factors that can act as triggers. This review provides a comprehensive discussion of the pathogenesis and treatment strategies of SLE and focuses on the progress

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… Moreover, sirolimus has demonstrated efficacy comparable to tacrolimus and MMF in the treatment of SLE or LN patients. … Sirolimus binds with high affinity to its cellular receptor, FKBP12, a 12-kilodalton protein that is notably overexpressed in T cells of individuals with lupus [ 263 ]. The sirolimus-FKBP12 complex inhibits the activation of the mammalian target of mTOR [ 264 ]. …

Targeted treatment of autoimmune cytopenias in primary immunodeficiencies.

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatm

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… Sirolimus showed efficacy for the treatment of AIC as second line off-label therapy, especially in ALPS patients. … Sirolimus/Everolimus are used for many other PIDs, such as CVID, ES, CTLA4 def ( 56 ), ARPC1B deficiency, to control autoimmune phenomena. …

Clinical management of cancer after kidney transplantation.

Advances in immunosuppressive therapy have markedly improved short-term graft survival post-kidney transplantation (KT); however, these advances have also profoundly altered long-term disease patterns in transplant recipients. Cancer remains a major barrier limiting improvements in long-term survival. Kidney transplant recipients are at increased risk of malignancy owing to impaired graft function and immunosuppressive medications. To improve cancer-related outcomes, comprehensive strategies encompassing prevention, early detection through screening, and appropriate treatment are required. Pri

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… A meta-analysis of individual patient data reported that sirolimus use was associated with a 40% and 56% reduction in overall cancer and NMSC risk, respectively ( 39 ). Conversion to sirolimus-based regimens was associated with even greater reductions in cancer incidence ( 39 ). … Sirolimus for secondary prevention of skin cancer in kidney transplant recipients: 5-year results . …

The neuroprotective role of eucalyptol in a type-2 diabetes induced neuropathy rat model.

This review aims to provide an extensive overview of the literature on the clinical pharmacokinetics of mycophenolate in solid organ transpl … bination with ciclosporin is approximately 30-40% lower than when given alone or with tacrolimus or sirolimus. High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA. Other co-medications can interfere with the absorption, enterohepatic recycling and metabolism of mycophenolate. Most pharmacokinetic investigations of MPA have …

PD 1 checkpoint inhibition in solid organ transplants: 2 sides of a coin - case report.

BACKGROUND: The management of malignancy post kidney transplantation includes reduction in immunosuppression and referral to an oncologist management of their malignancy. Recent advances in oncology have resulted in the approval of several classes of drugs with immune-modulatory activity. However, activation of the immune system against malignant cells may precipitate allograft rejection in solid organ transplant recipients. CASE PRESENTATION: Herein we present a case of acute kidney allograft rejection in a 50 year old man following administration of the novel immune-modulatory agent nivolum

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… In preparation, sirolimus was tapered off and prednisone was tapered to 5 mg daily, after which his allograft function remained stable with a creatinine of 1.4 mg/dL. His sirolimus level prior to discontinuation was 6.9 ng/mL. … His sirolimus level was noted to be 1 ng/mL and he was treated empirically for acute rejection with a 3 day methylprednisone pulse but without improvement. …

Ixazomib decreases the risk of chronic graft-versus-host disease: identification of cGVHD biomarkers.

AbstractChronic graft-versus-host disease (cGVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic stem cell transplantation. We hypothesize that it is possible to decrease its risk by manipulating the immune response in late phases of transplantation. We performed a prospective randomized trial including 73 patients. Patients in the treatment arm received 4 mg of ixazomib (IXZ) every 28 days from day +100. With a median follow-up of 24 months, the cumulative incidence of moderate/severe cGVHD in the IXZ vs control groups at 1 and 2 years were: 3.23% vs

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… ; Tk-MTX, tacrolimus-methotrexate; Tk-siro-MMF, tacrolimus-sirolimus-mycophenolate mofetil. … ; Tk-MTX, tacrolimus-methotrexate; Tk-siro-MMF, tacrolimus-sirolimus-mycophenolate mofetil …

The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand?

Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treat

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… Immunosuppressive regimens included concurrent prednisolone and the mTOR inhibitor sirolimus. … Tacrolimus was replaced by sirolimus before anti–PD-1, and serum sirolimus levels were initially maintained at lower levels (4–6 ng/mL) after anti–PD-1, and then increased to regimen values (10–12 ng/mL) 2 weeks after. …

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%

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… This outcome is consistent with the report that topical clobetasol treatment reduced aphthous ulceration in renal transplant patients receiving sirolimus 50 . … Woo , et al. 2015 Mammalian target of rapamycin inhibitor‐associated stomatitis in hematopoietic stem cell transplantation patients receiving sirolimus prophylaxis for graft‐versus‐host disease . Biol. …

Posttransplant complications: molecular mechanisms and therapeutic interventions.

Posttransplantation complications pose a major challenge to the long-term survival and quality of life of organ transplant recipients. These complications encompass immune-mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation.

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… Furthermore, mouse experiments by Shivaswamy et al. 174 demonstrated the damaging effects of tacrolimus treatment on pancreatic β‐cells and the inhibitory effects of sirolimus on insulin signaling. … A meta‐analysis by Yanik et al. 284 revealed that sirolimus use in renal transplant recipients was associated with a lower risk of renal carcinogenesis. …

Treatment-free survival to bortezomib combined with dexamethasone in patients with refractory/relapsed pure red cell aplasia: a prospective clinical study.

BackgroundImmunosuppressive treatments induce and maintain remissions in a majority of patients with acquired pure red cell aplasia (aPRCA); however, salvage therapy for non-responders remains unsatisfactory.MethodsIn this prospective, open-label, clinical trial (NCT04423367), patients with refractory/relapsed aPRCA were recruited and received subcutaneous bortezomib at 1.3 mg/m2 in combination with dexamethasone 40 mg weekly(BD regimen) for 12 weeks. The primary endpoint was the overall response rate at 12 weeks.ResultsIn total, 18 patients were enrolled, including 10 (55.6%) with primary aPR

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… Recently, several studies have underscored the potential benefits of sirolimus, a mammalian target of rapamycin (mTOR) inhibitor in patients who are refractory or CsA intolerant [ 9 , 10 ]. … Sirolimus has been shown to be an effective second-line option for patients with refractory or relapsed aPRCA, providing an ORR of 73.5% during a 12-month follow-up [ 9 ]. …

Monoclonal gammopathy of undetermined significance: a contraindication for living kidney donation?

During the last few years, the number of living donor kidney transplants has increased and this form of transplantation is currently the only option in some patients. We report two cases of living donor kidney transplantation in which the donor carried monoclonal gammopathy of undetermined significance. Neither of the two receptors has developed complications at 42 and 36 months after transplantation, respectively, and the donors have normal renal function and there is no evidence of progression to multiple myeloma.

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… Three months after the procedure, tacrolimus was switched to sirolimus due to the donor’s age and to minimize the risk of malignancy. The patient is currently receiving sirolimus and mycophenolate mofetil. To date, the patient has had no immunological or infectious complications. … Three months after transplantation, tacrolimus was switched to sirolimus for the same reasons as in Case 1. The patient is currently receiving sirolimus and mycophenolate mofetil. …

Prolonged haematologic toxicity in CAR-T-cell therapy: A review.

Chimeric antigen receptor-T-cell (CAR-T-cell) therapy is a novel immunotherapy with encouraging results for treatment of relapsed/refractory haematologic malignancies. With increasing use, our understanding of immune-mediated side effects such as cytokine release syndrome and neurotoxicity has improved; nevertheless, prolonged haematologic toxicity (PHT), with a high incidence rate, remains underrecognized. Owing to heterogeneity in populations, the CAR-T cells used and diseases treated as well as differences in the definition of PHT, its rate, risk factors and management vary across studies.

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… Sirolimus Sirolimus is an immunosuppressant that inhibits antigen‐induced T‐ and B‐cell proliferation and antibody production. … are needed to confirm the effectiveness and safety of sirolimus in treatment of PHT after CAR‐T‐cell therapy. …

Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide.

Background: Although the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically improved in the past decade, it is still compromised by transplant-related mortality (TRM), mainly caused by Graft-vs. -Host Disease (GvHD). Methods: We conducted a prospective observational study to ascertain the potential of serum interleukin-6 (IL6) levels, measured before conditioning and 7 days after allo-HSCT, in predicting acute GvHD, TRM and survival after allo-HSCT with Post-Transplant Cyclophosphamide (PT-Cy) based GvHD prophylaxis. Results: Between April 2014 and June

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… The study was limited to patients receiving PT-Cy and sirolimus as GvHD prophylaxis. … Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors. Leukemia. (2015) 29:396–405. 10.1038/leu.2014.180 17. …

Clinical Predictors of Response in Chronic Graft-Versus-Host Disease: Results From the "Predicting the Quality of Response to Specific Treatments (PQRST)" Trial.

Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying responses to treatment. The aim of this study was to identify predictors of treatment response. We conducted a prospective, observational cohort study of patients beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. We describe best and 6-month response rates, failure-free survival (FFS), and clinical predictors of response. Best response rates were 60%-70% to index therapies, which subsequently declined to 40% at 6 months. Sim

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… | 5 | 5.9 | MMF | 3 | 4.8 | ECP | 2 | 6.1 Belumosudil | 4 | 4.7 | Axatilimab | 1 | 1.6 | MMF | 1 | 3.0 Prednisone, CNI | 4 | 4.7 | Prednisone, Acalabrutinib | 1 | 1.6 | Prednisone | 1 | 3.0 Prednisone, MTX | 4 | 4.7 | Rituximab | 1 | 1.6 | Prednisone, MTX | 1 | 3.0 Sirolimus | 4 | 4.7 | Sirolimus | … 1 | 1.6 | Ruxolitinib, ECP | 1 | 3.0 Ibrutinib | 1 | 1.2 | Sirolimus, Ruxolitinib | 1 | 1.6 | Sirolimus, ECP | 1 | 3.0 CNI | 1 | 1.2 | | | | | | MMF | 1 | 1.2 | | | | | | MTX | 1 | 1.2 | | | | | | Prednisone, Belumosudil, Ruxolitinib | 1 | 1.2 | | | | | | Prednisone, MMF | 1 | …

Immunotherapeutic approaches for systemic lupus erythematosus: early overview and future potential.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Current SLE therapies include immunosuppressants, antimalarial drugs, non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids, but these treatments can cause substantial toxicities to organs and may not be effective for all patients. In recent years, significant progress has been made in the treatment of SLE using immunotherapy, including Benlysta and Saphnelo. These advances in immunotherapy hold promise for SLE patients, providing new therapeutic options that may offer better clinical benefit and effectiveness. S

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… Recently, treating active SLE patients with sirolimus improves disease activity, increases Tregs, and suppresses IL-4 and IL-17 generation without safety concerns [ 103 ]. … Crucially, sirolimus was well-tolerated among SLE patients [ 104 , 105 ]. However, the use of sirolimus requires caution, as it can lead to certain side effects and immune suppression, necessitating clinical monitoring. More research is needed to confirm sirolimus’s effectiveness for treating SLE. …

A new therapeutic approach in Gorham-Stout disease: a case report.

BackgroundGorham-Stout disease is a rare condition of unknown prevalence and unknown exact cause. Its pathogenesis is based on enhanced osteoclastic activity leading to bone resorption and bone replacement by distended lymphatic vessels. Because of its rarity and a various range of symptoms the disease may give, diagnosis is challenging and a strong index of suspicion is required. Although it is a benign condition, the prognosis may be unpredictable. The treatment options suggested so far are limited, and every case should be provided with the best individual approach. Herein, we present a cas

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… Several years later, our patient was commenced on treatment with sirolimus as it is proven to decrease the volume of lymphatic vessels in some patients, but unfortunately, no disease stabilization was achieved. … Gorham-Stout disease successfully treated with sirolimus (rapamycin): a case report and review of the literature. BMC Musculoskelet Disord. (2020) 21:577. 10.1186/s12891-020-03540-7 11. Brodszki N, Länsberg JK, Dictor M, Gyllstedt E, Ewers SB, Larsson MK, et al. …

Daratumumab monotherapy in refractory warm autoimmune hemolytic anemia and cold agglutinin disease.

AbstractAutoimmune hemolytic anemia (AIHA) is a rare autoantibody-mediated disease. For steroid and/or rituximab-refractory AIHA, there is no consensus on optimal treatment. Daratumumab, a monoclonal antibody targeting CD38, could be beneficial by suppression of CD38+ plasma cells and thus autoantibody secretion. In addition, because CD38 is also expressed by activated T cells, daratumumab may also act via immunomodulatory effects. We evaluated the efficacy and safety of daratumumab monotherapy in an international retrospective study including 19 adult patients with heavily pretreated refracto

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… , cyclosporin, danazole, methotrexate | Steroids Sirolimus Plasmapheresis | 4 | 140 | 4800 | 30 9 | 25/F | wAIHA DAT IgG>2+ | Evans syndrome | - | Steroids, rituximab, IVIG, bortezomib, sirolimus, danazol, EPO | Danazol Sirolimus | 6.3 | 19 | 421 | - 10 | 59/M | wAIHA DAT>2+ IgG | IgG MGUS | - | Steroids … This patient was heavily pretreated with immunosuppressive drugs and was still on prednisolone and sirolimus therapy when daratumumab treatment was initiated. …

Simultaneous loss of TSC1 and DEPDC5 in skeletal and cardiac muscles produces early-onset myopathy and cardiac dysfunction associated with oxidative damage and SQSTM1/p62 accumulation.

By promoting anabolism, MTORC1 is critical for muscle growth and maintenance. However, genetic MTORC1 upregulation promotes muscle aging and produces age-associated myopathy. Whether MTORC1 activation is sufficient to produce myopathy or indirectly promotes it by accelerating tissue aging is elusive. Here we examined the effects of muscular MTORC1 hyperactivation, produced by simultaneous depletion of TSC1 and DEPDC5 (CKM-TD). CKM-TD mice produced myopathy, associated with loss of skeletal muscle mass and force, as well as cardiac failure and bradypnea. These pathologies were manifested at eig

Rapamycin ameliorates corneal injury after alkali burn through methylation modification in mouse TSC1 and mTOR genes.

Alkali burn to the cornea is one of the most intractable injuries to the eye due to the opacity resulting from neovascularization (NV) and fibrosis. Numerous studies have focused on studying the effect of drugs on alkali-induced corneal injury in mouse, but fewer on the involvement of alkali-induced DNA methylation and the PI3K/AKT/mTOR signaling pathway in the mechanism of alkali-induced corneal injury. Thus, the aim of this study was to determine the involvement of DNA methyltransferase 3 B-madiated DNA methylation and PI3K/AKT/mTOR signaling modulation in the mechanism of alkali-induced cor

Kindlin-3 interacts with the ribosome and regulates c-Myc expression required for proliferation of chronic myeloid leukemia cells.

Kindlins are FERM-containing cytoplasmic proteins that regulate integrin-mediated cell-cell and cell-extracellular matrix (ECM) attachments. Kindlin-3 is expressed in hematopoietic cells, platelets, and endothelial cells. Studies have shown that kindlin-3 stabilizes cell adhesion mediated by ß1, ß2, and ß3 integrins. Apart from integrin cytoplasmic tails, kindlins are known to interact with other cytoplasmic proteins. Here we demonstrate that kindlin-3 can associate with ribosome via the receptor for activated-C kinase 1 (RACK1) scaffold protein based on immunoprecipitation, ribosome binding,