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Organ transplant is often the treatment of choice as it extends and improves patient life. Immunosuppressive treatment, which prevents acute rejection of the organ, is used in transplant patients to prevent the loss of transplant. The aim of the study was to determine the impact of the CTLA4 (+49A>G, rs231775) and the TGF-β1 (-800G>A, rs1800468) polymorphisms on the therapeutic effect of immunosuppressive drugs (cyclosporine-CsA, tacrolimus-TAC) and the risk of acute rejection in renal transplant patients. The analysis of the CTLA4 +49A>G and the TGF-β1 -800G>A polymorphisms was carried out in 392 patients after kidney transplant using real-time PCR. The CTLA4 +49A>G polymorphism did not affect CsA or TAC dose, ratio of drug concentration to dose (C/D), and blood concentrations. As for the TGF-β1 -800G>A polymorphism, patients with the GA genotype required lower TAC doses compared to the GG genotype (TAC 12 h: 3.63 mg vs 5.3 mg, TAC 24 h: 2.38 mg vs 3.29 mg). Comparing the C/D ratio in both groups (TAC 12 h and TAC 24 h), higher C/D ratio was observed in patients with the GA genotype. These results indicate that patients with the A allele require slightly lower doses of TAC. The results suggest that the TGF-β1 -800 G>A polymorphism may influence the TAC dose, while the +49A>G polymorphism of the CTLA4 gene does not correlate with the dose of CsA or TAC. The analysis of the biochemical parameters of the renal profile showed no impact of the CTLA4 and the TGF-β1 polymorphisms on the risk of organ rejection., (© 2021. The Author(s).)

Objectives: To analyse the current evidence for the management of lupus nephritis (LN) informing the 2019 update of the EULAR/European Renal Association-European Dialysis and Transplant Association recommendations., Methods: According to the EULAR standardised operating procedures, a PubMed systematic literature review was performed, from January 1, 2012 to December 31, 2018. Since this was an update of the 2012 recommendations, the final level of evidence (LoE) and grading of recommendations considered the total body of evidence, including literature prior to 2012., Results: We identified 387 relevant articles. High-quality randomised evidence supports the use of immunosuppressive treatment for class III and class IV LN (LoE 1a), and moderate-level evidence supports the use of immunosuppressive treatment for pure class V LN with nephrotic-range proteinuria (LoE 2b). Treatment should aim for at least 25% reduction in proteinuria at 3 months, 50% at 6 months and complete renal response (<500-700 mg/day) at 12 months (LoE 2a-2b). High-quality evidence supports the use of mycophenolate mofetil/mycophenolic acid (MMF/MPA) or low-dose intravenous cyclophosphamide (CY) as initial treatment of active class III/IV LN (LoE 1a). Combination of tacrolimus with MMF/MPA and high-dose CY are alternatives in specific circumstances (LoE 1a). There is low-quality level evidence to guide optimal duration of immunosuppression in LN (LoE 3). In end-stage kidney disease, all methods of kidney replacement treatment can be used, with transplantation having the most favourable outcomes (LoE 2b)., Conclusions: There is high-quality evidence to guide the initial and subsequent phases of class III/IV LN treatment, but low-to-moderate quality evidence to guide treatment of class V LN, monitoring and optimal duration of immunosuppression., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune-stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll-like receptor 4 (TLR4) complex, but it was not known whether its immuno-modulatory and antitumor functions involved entry by this same route., Methods: The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild-type (WT) mice, TLR4 -/- mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively., Results: Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB-stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up-regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4 + cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4 + and CD8 + T cells in splenocytes from WT mice, but not from TLR4-deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4 -/- littermates., Conclusions: The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Calcineurin (protein phosphatase 3) regulates synaptic plasticity in the brain. The development of neuropathic pain appears dependent on some of the same mechanisms that underlie brain synaptic plasticity. In this study, we examined whether calcineurin regulates chronic constriction injury (CCI)-elicited plasticity in the spinal dorsal horn. CCI animals exhibited mechanical and thermal hypersensitivity 7 days after ligation of the sciatic nerve. Neither control uninjured nor sham-operated animals exhibited pain behavior. Calcineurin activity and content of its Aα isoform were significantly decreased in the ipsilateral postsynaptic density (PSD) of dorsal horn neurons in CCI animals. Calcineurin activity and content in the contralateral PSD of CCI animals or either side of the dorsal horn in sham animals were not modified. The pain behavior in CCI animals was attenuated by intrathecal application of exogenous calcineurin. The treatment was long-lasting as a single injection provided analgesia for 4 days by restoring the phosphatase's activity and Aα content in the PSD. No signs of toxicity were detected up to 14 days after the single intrathecal injection. Intrathecal application of the calcineurin inhibitor FK-506 elicited pain behavior in control uninjured animals and significantly reduced calcineurin activity in the PSD. CCI may elicit neuropathic pain at least in part as a result of the loss of calcineurin-mediated dephosphorylation in the dorsal horn. Addition of the phosphatase by intrathecal injection reverses the injury-elicited loss and provides prolonged pain relief. Clinical therapy with calcineurin may prove to be a novel, effective, and safe approach in the management of well-established neuropathic pain., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: Withholding calcineurin inhibitors (CNIs) can be considered when graft function is inadequate following kidney transplantation (KT). Thymoglobulin (rATG) can be used to prevent acute rejection while CNIs are being withheld. Here, we report our results of a novel CNI-sparing induction protocol, which utilizes a CD3+ cell count-based rATG treatment regimen when delayed graft function (DGF) develops in the immediate postoperative period., Methods: In a cohort of 153 consecutive deceased-donor KT recipients, all received a single intraoperative dose of basiliximab; 84 subsequently developed DGF and therefore received rATG (rATG+ group), while 69 demonstrated immediate graft function and received CNIs (rATG- group)., Results: In the rATG+ group, mean duration of therapy was 8.5±6.0 d, permitting CNI initiation to be delayed until postoperative day 10.3±6.2. Cumulative dose of rATG was only 5.1±4.5 mg/kg while targeting CD3+ counts of ≤30 cells/mm3. CD3+ counts were reduced to a mean of 16.7±17.0 cells/mm3 during therapy. At one yr, patient and graft survival rates were 97.6% and 92.9%, respectively, while the frequency of infections and malignancies were not significantly increased compared to the rATG- group., Conclusion: A unique induction regimen successfully delayed CNI initiation by using modest doses of rATG to deplete CD3+ cells, while yielding excellent long-term graft outcome without increased risk of infection or malignancy., (© 2012 John Wiley & Sons A/S.)

We showed previously that calcineurin B subunit (CnB) protein activates innate immune cells including macrophages, monocytes and dendritic cells and acts as an adjuvant of a model antigen (ovalbumin) and a recombinant pneumolysin antigen, but the detailed mechanism is not clear and whether it can serve as an adjuvant of a commercial HBV vaccine is unknown. Here, we report that CnB promotes inflammatory cytokines production, splenocytes proliferation and NK lytic activity, and that CnB-induced inflammatory cytokines (IFN-γ, IL-6, TNF-α) production is dependent on integrin αM. Animal experiments demonstrate that CnB markedly increases the total anti-HBs antibodies in a dose and time dependent manner. Furthermore, CnB increases both anti-HBs IgM and anti-HBs IgG titers and changes the balance of IgG2a and IgG1. Combined use of CnB and CpG induces more cytokines production in splenocytes, as well as more anti-HBs antibodies production in vivo. These results reveal a probable mechanism of CnB-induced inflammatory cytokines production and further demonstrate that CnB is a novel and effective adjuvant of Engerix-B HBV vaccine., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Single nucleotide polymorphisms (SNPs) in the transforming growth factor-β1 gene (TGFB1) have been inconsistently associated with calcineurin inhibitor (CNI)-induced renal dysfunction following cardiac transplantation. The impact of genetic variants related to the renin-angiotensin-aldosterone system (RAAS) and natriuretic peptides, which are implicated in CNI nephrotoxicity, is unknown. The primary objective of this study was to validate the association between two common variants in TGFB1 (rs1800470, rs1800471) and postcardiac transplant renal function. The secondary objective was to investigate the effect of candidate genes related to the RAAS, natriuretic peptides, and other elements involved in the intracellular signaling of these pathways., Methods: We conducted a retrospective cohort study of 158 heart transplant recipients treated with CNIs, and evaluated the association between select SNPs and the estimated glomerular filtration rate as calculated by the Modification of Diet in Renal Disease simplified formula. A total of 273 SNPs distributed in 44 genes were tested., Results: No association was observed between TGFB1 variants and renal function. One polymorphism in the protein kinase C-β gene (PRKCB; rs11074606), which is implicated in the RAAS intracellular signaling, was significantly associated with post-transplant estimated glomerular filtration rate after adjusting for possible confounders (P=0.00049). This marker is in linkage disequilibrium with two variants located in putative regulatory regions of the gene (rs2283541, rs1013316)., Conclusion: Our results suggest that PRKCB may be a potential predictor of CNI-induced nephrotoxicity in heart transplant recipients, and could therefore be a promising candidate to identify patients who are most susceptible to this adverse drug reaction.

Protective immunity involves a dynamic balance between humoral and cellular immune responses. In the present work we demonstrated that recombinant human calcineurin subunit B (rhCnB) stimulated the expression of the surface molecules CD83, CD80, CD86, CD40, and HLA-DR. It also promoted secretion of inflammatory cytokines IL-6, TNF-α, and IL-1β by human PBMC-derived dendritic cells. In in vivo experiments, splenocytes from BALB/c mice immunized with pneumolysin plus rhCnB contained a higher percentage of CD3(+)CD4(+) T lymphocytes, produced more antigen-specific splenocyte proliferation activity, and had higher anti-pneumolysin immunoglobulin G (IgG) titers. Transcript levels of cytokines such as IL-4, IL-10, and IFN-γ in the splenocytes were also upregulated when in vitro stimulated with pneumolysin. Thus, rhCnB promoted a mixed Th1/Th2 type immune response when given together with the specific antigen PN. RhCnB could have potential as a prophylactic vaccine adjuvant., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This report describes a group of pediatric liver transplant recipients who have undergone once daily calcineurin inhibitor (CNI) monotherapy at Children's Memorial Hospital, Chicago, between January 1, 2001 and November 30, 2008. We defined success as normal liver enzymes at 1 year after dose change, with normal enzymes throughout all follow-up. Patients who did not meet the set criteria or had lost an organ to chronic rejection were not considered for this therapeutic strategy. There were 147 patients in our organ transplant tracking record (OTTR) who were > or = 5 years post liver transplant. Of these, 56 underwent reduced dose, once daily CNI monotherapy. Patients who met the set criteria were placed on once daily calcineurin inhibitor at half their previous dose. Fifty patients successfully achieved this dose change, while six patients failed at a mean of 3.7 +/- 3.2 months following the dosing change. The mean interval from transplant was significantly longer in those patients who were successful compared to those who failed dose change (p < 0.05). Importantly, there have been no graft losses. Reduced dose, once daily CNI monotherapy is safe in carefully selected recipients, with a longer interval post liver transplantation increasing the likelihood of success.

Using a clinically relevant, fully disparate, allogeneic aortic transplant mouse model of allograft vasculopathy, we have demonstrated that neointimal proliferation is dependent on CD8(+) T cell effector pathways in the presence of therapeutic doses of calcineurin inhibitor (CNI) immunosuppression. CD4(+) T cell pathways are ablated by CNI immunosuppression. In the current study, we examined the relationship between CD8(+) T cell activities, medial SMC loss and neointimal hyperplasia. We demonstrate that at 5-6wk post transplantation in a wild type/wild type transplant CD8(+) T cell infiltration, CD8(+) CTL effector cell mediator expression and medial SMC loss all occur within aortic interposition grafts in the face of CNI immunosuppression. Both IFN-gamma and CTL mediated effector function is required for SMC loss and lesion formation under these conditions. Using strain combinations and reconstitution models, we provide data that blockade of the perforin/granzyme pathway does not prevent lesion formation but that blockade of the Fas/FasL pathway of cytotoxicity dramatically reduces SMC loss and prevents neointimal lesion formation. Both of these blockade strategies are in the face of an active IFN-gamma pathway. These data suggest a cooperative role between Fas/FasL and IFN-gamma mediated effector functions in medial SMC loss and neointimal lesion formation., (Copyright 2009 Elsevier B.V. All rights reserved.)

Topical calcineurin inhibitors have developed a bad connotation because of a black-box warning that was based on safety concerns of hypothetic systemic absorption and because systemic treatment with calcineurin inhibitors in patients who receive organ transplants is associated with an increased cancer risk. A few case reports of lymphoma and skin cancer in patients treated with topical calcineurin inhibitors initiated the discussion. These drugs were recommended for use as second-line therapy for the short-term and noncontinuous treatment of atopic dermatitis in patients who do not respond adequately to topical corticosteroids or in whom they are contraindicated. According to the latest knowledge, there is no scientific evidence of an increased risk for malignancy due to a topical treatment with calcineurin inhibitors., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose of Review: The following study reviews the recent literature pertaining to allergic contact dermatitis (ACD) in the pediatric population. This study also provides an overview of the most common allergens and discusses various therapeutic modalities., Recent Findings: The pathophysiology of ACD is intricate and multifaceted, resulting in a characteristic, delayed inflammatory response. Although commonly recognized in adults, its existence in the pediatric population was questioned. Recent literature suggests that pediatric ACD exists and is more common than previously recognized. The diagnosis relies on the clinical presentation combined with appropriate use and interpretation of a patch test. Although many studies have investigated ACD in children, few have documented the relevance of positive patch test reactions until recently. The most current prevalence estimates of positive patch test reactions range from 14 to 70% of children patch tested. Although that range is broad, these studies have demonstrated the relevance of positive reactions and confirmed ACD as a disease entity in children., Summary: ACD is a previously underrecognized disease process in the pediatric population that can manifest as a serious dermatologic challenge for both patients and physicians. This review will address the prevalence, diagnostic methods, frequent allergens and treatment options in pediatric ACD.

Background: Chronic steroid therapy in spite of myriad side effects is widely used in kidney transplantation. This prospective controlled study evaluated safety and efficacy of steroid withdrawal at 2 days in kidney recipients monitored by surveillance biopsy., Methods: In all, 300 kidney recipients were studied; 150 in second-day steroid withdrawal group and 150 in steroid treated group (control group). Immunosuppression was basiliximab induction and maintenance was a calcineurin inhibitor and mycophenolate mofetil or sirolimus. Biopsy-proven acute rejection (BPAR) was treated by methylpredisolone. Surveillance biopsies were completed to evaluate subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Primary end point was acute rejection. Three-year patient and graft survival, new onset diabetes mellitus (NODM), serum creatinine and creatinine clearance were evaluated., Results: Acute rejection was diagnosed in 14% in control group and 16% in steroid withdrawal group. Three-year patient and graft survival was 89% and 79% in control and 91% and 78% in steroid withdrawal group. Serum creatinine and creatinine clearance was 1.9+/-0.8 and 59+/-11 in control group and 1.8+/-0.9 mg/dl and 61+/-10 mls/minute in steroid withdrawal group. Incidence of SCAR and progression of CAN were comparable in the 2 groups. At 3-years NODM was diagnosed in 21% in control group and 4% in steroid withdrawal group (P<0.01)., Conclusions: Two-day steroid withdrawal in kidney transplant recipients did not affect BPAR, SCAR, CAN, graft function and patient and graft survival compared to control group up to 3 years. NODM was significantly less in steroid withdrawal group. Two-day steroid withdrawal is safe and beneficial in kidney transplant recipients.

Atopic dermatitis is a common chronic inflammatory skin disease often preceding the development of asthma and allergic disorders, such as food allergy or allergic rhinoconjunctivitis. Pathophysiology involves a complex series of interactions between resident and infiltrating cells orchestrated by proinflammatory cytokines and chemokines. A deficiency of antimicrobial peptides might contribute to the propensity for colonization or infection by microbial organisms seen in atopic dermatitis. New treatment approaches include use of topical steroids as maintenance therapy and use of topical calcineurin inhibitors for early intervention with topical steroids used as rescue therapy.

Calcineurin (CN) is a Ca (2+)/calmodulin-stimulated protein phosphatase. It is a heterodimeric enzyme consisting of a catalytic subunit (CN A) and a Ca2+ -binding regulatory subunit (CN B), which plays an important role in the human immune system. Its regulatory subunit, CN B, on its own, was found to have a remarkable anticancer effect in mice. To clarify the basis of this action the in vivo and in vitro effect of CN B on several types of mice immunocytes was investigated. The phagocytic activity of peritoneal macrophages of both normal mice and mice bearing S 180 solid tumors increased when CN B was injected daily. In vitro examination using a modified MTT assay and an [3H] incorporation assay showed that the cytotoxicity of peritoneal macrophages was increased substantially. CN B also increased the natural killer activity of murine spleen lymphocytes in vivo and in vitro, and synergized with concanavalin A in stimulating their proliferation. Our results indicate that CN B has a significant stimulatory action on the immune system that may partially account for its anticancer activity.

Atopic dermatitis (AD) is a common skin disorder whose prevalence has increased, similarly to other atopic diseases. The immunopathogenesis of AD is complex, although Staphylococcus aureus may play an important role in cutaneous inflammation, possibly resulting from a deficiency in antimicrobial peptide secretion in the skin. Although more than 50% of patients will go on to develop asthma and allergies, atopic dermatitis is often the start of the "atopic march." Studies with topical fluticasone provide a rationale for maintenance therapy, whereas studies with the topical nonsteroidal immunomodulator pimecrolimus in patients as young as 3 months of age suggest that early intervention may be an effective strategy in treating this chronic, relapsing skin disease.