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Impact of low disease activity, remission, and complete remission on flares following tapering of corticosteroids and immunosuppressive therapy in patients with systemic lupus erythematous: a multinational cohort study

Cho J, Shen L, Huq M, Kandane-Rathnayake R, Golder V, Louthrenoo W, et al.

Lancet Rheumatol, 2023 Oct;5(10):e584-e593.
PMID: 38251484 DOI: 10.1016/S2665-9913(23)00209-6

BACKGROUND: Targets of treatment for systemic lupus erythematosus (SLE) include the Lupus Low Disease Activity State (LLDAS), remission, and complete remission. Whether treatment can be tapered after attaining these targets and whether tapering is safer in patients in complete remission compared with LLDAS are unknown. We aimed to assess the odds of disease flares after treatment tapering in stable disease, versus continuing the same therapy. We also aimed to examine whether tapering in complete remission resulted in fewer flares or longer time to flare compared with tapering in LLDAS or remission.
METHODS: This multinational cohort study was conducted at 25 sites across 13 Asia-Pacific countries. We included adult patients aged 18 years or older with stable SLE who were receiving routine clinical care, had two or more visits and had attained stable disease at one or more visits. We categorised stable disease into: LLDAS (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] score ≤4, Physician Global Assessment [PGA] ≤1, and prednisolone ≤7·5 mg/day); Definitions of Remission in SLE (DORIS) remission (clinical SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day); or complete remission on therapy (SLEDAI-2K score 0, PGA <0·5, and prednisolone ≤5 mg/day). Stable disease categories were mutually exclusive. Tapering was defined as any decrease in dose of corticosteroids or immunosuppressive therapy (mycophenolate mofetil, calcineurin inhibitors, azathioprine, leflunomide, or methotrexate). Using multivariable generalised estimating equations, we compared flares (SELENA-SLEDAI Flare Index) at the subsequent visit after drug tapering. We used generalised estimating equations and Cox proportional hazard models to compare tapering attempts that had begun in LLDAS, remission, and complete remission.
FINDINGS: Between May 1, 2013, and Dec 31, 2020, 4106 patients were recruited to the cohort, 3002 (73·1%) of whom were included in our analysis. 2769 (92·2%) participants were female, 233 (7·8%) were male, and 2636 (88·1%) of 2993 with ethnicity data available were Asian. The median age was 39·5 years (IQR 29·0-50·0). There were 14 808 patient visits for patients in LLDAS, or remission or complete remission, of which 13 140 (88·7%) entered the final multivariable model after excluding missing data. Among the 9863 visits at which patients continued the same therapy, 1121 (11·4%) flared at the next visit, of which 221 (19·7%) were severe flares. Of the 3277 visits at which a patient received a tapering of therapy, 557 (17·0%) flared at the next visit, of which 120 (21·5%) were severe flares. Tapering was associated with higher odds of flare compared with continuing the same therapy (odds ratio [OR] 1·24 [95% CI 1·10-1·39]; p=0·0005). Of 2095 continuous tapering attempts, 860 (41·1%) were initiated in LLDAS, 596 (28·4%) in remission, and 639 (30·5%) in complete remission. Tapering initiated in LLDAS (OR 1·37 [95% CI 1·03-1·81]; p=0·029) or remission (1·45 [1·08-1·94]; p=0·013) had higher odds of flare in 1 year compared with complete remission. Tapering in LLDAS (hazard ratio 1·24 [95% CI 1·04-1·48]; p=0·016) or remission (1·30 [1·08-1·56]; p=0·0054) had a significantly shorter time to first flare than tapering initiated in complete remission. Attaining sustained LLDAS, remission, or complete remission for at least 6 months just before the time of taper was associated with lower odds of flare at next visit, flares in 1 year, and longer time to flare.
INTERPRETATION: Tapering of corticosteroids or immunosuppressive therapy in patients with stable SLE was associated with excess flares. Our findings suggest that drug tapering should be carefully considered, weighing the risks and benefits, and is best exercised in complete (clinical and serological) remission and after maintaining stable disease for at least 6 months.
FUNDING: AstraZeneca, BMS, Eli Lily, Janssen, Merck Serono, GSK, and UCB.

Matched MeSH terms: Immunosuppression
Fulltext PIP4Ks impact on PI3K, FOXP3, and UHRF1 signaling and modulate human regulatory T cell proliferation and immunosuppressive activity

Poli A, Abdul-Hamid S, Zaurito AE, Campagnoli F, Bevilacqua V, Sheth B, et al.

Proc Natl Acad Sci U S A, 2021 08 03;118(31).
PMID: 34312224 DOI: 10.1073/pnas.2010053118

Regulatory T cells (Tregs) play fundamental roles in maintaining peripheral tolerance to prevent autoimmunity and limit legitimate immune responses, a feature hijacked in tumor microenvironments in which the recruitment of Tregs often extinguishes immune surveillance through suppression of T-effector cell signaling and tumor cell killing. The pharmacological tuning of Treg activity without impacting on T conventional (Tconv) cell activity would likely be beneficial in the treatment of various human pathologies. PIP4K2A, 2B, and 2C constitute a family of lipid kinases that phosphorylate PtdIns5P to PtdIns(4,5)P 2 They are involved in stress signaling, act as synthetic lethal targets in p53-null tumors, and in mice, the loss of PIP4K2C leads to late onset hyperinflammation. Accordingly, a human single nucleotide polymorphism (SNP) near the PIP4K2C gene is linked with susceptibility to autoimmune diseases. How PIP4Ks impact on human T cell signaling is not known. Using ex vivo human primary T cells, we found that PIP4K activity is required for Treg cell signaling and immunosuppressive activity. Genetic and pharmacological inhibition of PIP4K in Tregs reduces signaling through the PI3K, mTORC1/S6, and MAPK pathways, impairs cell proliferation, and increases activation-induced cell death while sparing Tconv. PIP4K and PI3K signaling regulate the expression of the Treg master transcriptional activator FOXP3 and the epigenetic signaling protein Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). Our studies suggest that the pharmacological inhibition of PIP4K can reprogram human Treg identity while leaving Tconv cell signaling and T-helper differentiation to largely intact potentially enhancing overall immunological activity.

Matched MeSH terms: Immunosuppression
Fulltext Better outcome of COVID-19 positive kidney transplant recipients during the unremitting stage with optimized anticoagulation and immunosuppression

AlOtaibi TM, Gheith OA, Abuelmagd MM, Adel M, Alqallaf AK, Elserwy NA, et al.

Clin Transplant, 2021 Jun;35(6):e14297.
PMID: 33768630 DOI: 10.1111/ctr.14297

INTRODUCTION: COVID-19 is an ongoing pandemic with high morbidity and mortality and with a reported high risk of severe disease in kidney transplant recipients (KTR).
AIM: We aimed to report the largest number of COVID-19-positive cases in KTR in a single center and to discuss their demographics, management, and evolution.
METHODS: We enrolled all the two thousand KTR followed up in our center in Kuwait and collected the data of all COVID-19-positive KTR (104) from the start of the outbreak till the end of July 2020 and have reported the clinical features, management details, and both patient and graft outcomes.
RESULTS: Out of the one hundred and four cases reported, most of them were males aged 49.3 ± 14.7 years. Eighty-two of them needed hospitalization, of which thirty-one were managed in the intensive care unit (ICU). Main comorbidities among these patients were hypertension in 64.4%, diabetes in 51%, and ischemic heart disease in 20.2%. Management strategies included anticoagulation in 56.7%, withdrawal of antimetabolites in 54.8%, calcineurin inhibitor (CNI) withdrawal in 33.7%, the addition of antibiotics in 57.7%, Tocilizumab in 8.7%, and antivirals in 16.3%. During a follow-up of 30 days, the reported number of acute kidney injury (AKI) was 28.7%, respiratory failure requiring oxygen therapy 46.2%, and overall mortality rate was 10.6% with hospital mortality of 13.4% including an ICU mortality rate of 35.5%.
CONCLUSION: Better outcome of COVID-19-positive KTR in our cohort during this unremitting stage could be due to the younger age of patients and early optimized management of anticoagulation, modification of immunosuppression, and prompt treatment of secondary bacterial infections. Mild cases can successfully be managed at home without any change in immunosuppression.

Matched MeSH terms: Immunosuppression
Immunomodulatory effect of Noni fruit and its isolates: insights into cell-mediated immune response and inhibition of LPS-induced THP-1 macrophage inflammation

Ezzat MI, Hassan M, Abdelhalim MA, El-Desoky AM, Mohamed SO, Ezzat SM

Food Funct, 2021 Mar 18.
PMID: 33734250 DOI: 10.1039/d0fo03402a

Morinda citrifolia L. is a plant of the family Rubiaceae and is known as Indian mulberry or Noni in India. It is a perennial herb native to Southeast Asia and has been used over the years as a food supplement and medicinal plant. Noni fruits are reported to possess anticancer, fungicidal, antiviral and antiarthritic effects. The objective of our study is the screening of the immunomodulatory activity of the total extract, fractions, and isolated compounds of Noni fruits to identify their bioactive compounds. To achieve our goal, an ethanol extract (EE) was prepared from Noni fruits. Fractionation and purification of the EE were accomplished. The cell-mediated immune (CMI) response in prednisolone-induced immunosuppression rats was evaluated. The toxicity of the EE, fractions and isolated compounds on the differentiated THP-1 macrophage was assessed using the MTT viability assay. Moreover, the inflammation-related immune responses in lipopolysaccharide (LPS)-induced THP-1 macrophage activation were evaluated. Fractionation of the EE gave three fractions, dichloromethane (DCMF), water (WF) and methanol (MF). Purification of DCMF yielded stigmast-7-ene-3-ol (M1), 28-hydroxy-3β-acetoxy-9-dehydrogramisterol (M2), 3β-acetoxy-taraxast-20(30)-ene-21-ol (M3), 22-dehydroclerosterol (M4) and 22-dehydroclerosterol-3-O-β-d-glucopyranoside (M5), while purification of MF yielded quercetin (M6), hesperidin (M7), naringin (M9) and gallic acid (M8). The results revealed that DCMF elicited an increase in paw edema to the extent of 35.8%. All the tested samples had no cytotoxic effect on THP-1 macrophages. Co-treatment of the LPS-induced macrophages with DCMF, M2, M3, and M6 decreased the production of TNF-α, IL-1β, and IL-6/IL-10. The expression of iNOS, COX-2, and NF-κB decreased to 0.14 ± 0.02, 0.15 ± 0.02, and 0.17 ± 0.03, respectively, after co-treatment with LPS and DCMF. M2 attenuated the expression of iNOS and NF-κB to 0.18 ± 0.03 and 0.17 ± 0.03, respectively. Additionally, M3 attenuated the expression of iNOS to 0.18 ± 0.03, and after co-treatment with M6 and LPS, the expression of COX-2 and NF-κB was down-regulated to 0.2 ± 0.03. Our study proves the immunomodulatory effect of Noni fruits and specifies for the first time the compounds responsible for their activity.

Matched MeSH terms: Immunosuppression
Fulltext Asymptomatic Lymphocytic Interstitial Pneumonia with Extensive HRCT Changes Preceding Sjogren's Syndrome

Baharuddin H, Hanafiah M, Aflah SSS, Zim MAM, Ch'Ng SS

Case Rep Pulmonol, 2021;2021:6693031.
PMID: 33505755 DOI: 10.1155/2021/6693031

Lymphocytic interstitial pneumonia (LIP) is a rare condition, commonly associated with Sjogren's syndrome (SS). We report a 53-year-old woman with an incidental finding of an abnormal chest radiograph. LIP was diagnosed based on high-resolution computed tomography and lung biopsy, but treatment was not initiated. Six years later, she developed cough and dyspnoea, associated with dry eyes, dry mouth, and arthralgia. While being investigated for the respiratory symptoms, she developed cutaneous vasculitis and was treated with 1 mg/kg prednisolone, which resulted in the improvement of her respiratory symptoms. Physical examination revealed fine bibasal crepitations, active vasculitic skin lesions, and a positive Schirmer's test. Investigations revealed a restrictive pattern in the pulmonary function test, stable LIP pattern in HRCT, and positive anti-Ro antibodies. She was treated with prednisolone and azathioprine for 18 months, and within this time, she was hospitalised for flare of LIP, as well as respiratory tract infection on three occasions. During the third flare, when she also developed cutaneous vasculitis, she agreed for prednisolone but refused other second-line agents. To date, she remained well with the maintenance of prednisolone 2.5 mg monotherapy for more than one year. The lessons from this case are (i) patients with LIP can be asymptomatic, (ii) LIP can precede symptoms of SS, and (iii) treatment decision for asymptomatic patients with abnormal imaging or patients with mild severity should be weighed between the risk of immunosuppression and risk of active disease.

Matched MeSH terms: Immunosuppression
Fulltext Assessing the Immunomodulatory Activity of Ethanol Extract of Sambucus javanica Berries and Leaves in Chloramphenicol-Induced Aplastic Anemia Mouse Model

Putra WE, Rifa'i M

Trop Life Sci Res, 2020 Jul;31(2):175-185.
PMID: 32922674 DOI: 10.21315/tlsr2020.31.2.9

Aplastic anemia, life-threatened disease, is a hematologic disorder characterised by bone marrow hypoplasia. Multiple modalities such as bone marrow transplantation and immunosuppression treatment have been proposed to ameliorate this entity, however it remains ineffective. Sambucus, a group of herb plants, possesses a broad spectrum of medicinal properties such as antioxidant, insulin-like activity, anticancer and antiviral. However, the study about its activity toward aplastic anemia incidence is based on limited data. Thus, the research aim of this study was to evaluate the immunomodulatory activities of Sambucus javanica in chloramphenicol-induced anemia aplastic mouse model. In this present study, BALB/c mice were administrated with chloramphenicol (CMP) to induce aplastic anemia then followed by S. javanica extracts treatment. Additionally, cellular and molecular aspects were evaluated by flow cytometry and Hematoxylin-Eosin staining. Further analysis showed that S. javanica extracts could promote the population number of regulatory T-cells and naive cytotoxic T-cells. Moreover, those extract also reduced the inflammation and necrotic incidence in CMP-induced mouse aplastic anemia model. Together, these results suggest that S. javanica has therapeutically effect to aplastic anemia by altering the immune system as an immunomodulatory agent.

Matched MeSH terms: Immunosuppression
Low Immunologic Risk Living Related Renal Transplant Using Very Low-Dose Antithymocyte Globulin as Induction Therapy: A Single Tertiary Hospital Experience

Jalalonmuhali M, Ng KP, Ong CS, Lee YW, Wan Md Adnan WAH, Lim SK

Transplant Proc, 2020 05 21;52(6):1709-1714.
PMID: 32448669 DOI: 10.1016/j.transproceed.2020.02.139

The aim of induction therapy in the management of kidney transplant is to reduce the incidence of acute rejection and delayed graft function after kidney transplant. The agent for induction therapy differs depending on the recipient risks. The regimen can be either polyclonal (rabbit antithymocyte globulin [rATG]) or monoclonal antibody (basiliximab). Basiliximab is commonly used in patients with low immunologic risk. However, to date we know that the use of rATG on T cell depletion is dose dependent and more potent antirejection therapy. Therefore, we would like to look at 1-year graft function of very low-dose rATG in low immunologic risk recipients. All low immunologic risk patients who received low-dose rATG (0.5 mg/kg of body weight daily) during transplant (day 0) and on days 1 and 2 were recruited. Their renal function, HLA donor-specific antibodies, lymphocyte counts, protocol biopsy results, and cytomegalovirus (CMV) polymerase chain reaction were monitored as per clinical practice. All 10 patients had immediate graft function. Low-dose rATG caused lymphocyte counts to deplete immediately on day 0, and the effect lasted about 1 month post-transplant. All the patients had stable graft function without any significance episode of rejection. Only one patient had de novo HLA-DQ antibody. It is good to know that without prophylaxis antiviral in CMV+ donor to CMV+ recipient, the incidence of CMV viremia is considerably low in our cohort. Very low-dose rATG is an effective induction immunosuppression in low immunologic risk patients with acceptable infection risk.

Matched MeSH terms: Immunosuppression/methods*
Characteristics and clinical applications of Wharton's jelly-derived mesenchymal stromal cells

Liau LL, Ruszymah BHI, Ng MH, Law JX

Curr Res Transl Med, 2020 01;68(1):5-16.
PMID: 31543433 DOI: 10.1016/j.retram.2019.09.001

Mesenchymal stromal cells (MSCs) are widely used in the clinic because they involve fewer ethical issues and safety concerns compared to other stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). MSCs derived from umbilical cord Wharton's jelly (WJ-MSCs) have excellent proliferative potential and a faster growth rate and can retain their multipotency for more passages in vitro compared to adult MSCs from bone marrow or adipose tissue. WJ-MSCs are used clinically for repairing tissue injuries of the spinal cord, liver and heart with the aim of regenerating tissue. On the other hand, WJ-MSCs are also used clinically to ameliorate immune-mediated diseases based on their ability to modulate immune responses. In the field of tissue engineering, WJ-MSCs capable of differentiating into multiple cell lineages have been used to produce a variety of engineered tissues in vitro that can then be transplanted in vivo. This review discusses the characteristics of WJ-MSCs, the differences between WJ-MSCs and adult MSCs, clinical studies involving WJ-MSCs and future perspectives of WJ-MSC research and clinical applications. To summarize, WJ-MSCs have shown promise in treating a variety of diseases clinically. However, most clinical trials/studies reported thus far are relatively smaller in scale. The collected evidence is insufficient to support the routine use of WJ-MSC therapy in the clinic. Thus, rigorous clinical trials are needed in the future to obtain more information on WJ-MSC therapy safety and efficacy.

Matched MeSH terms: Immunosuppression
Fulltext Disease risk analysis in sea turtles: A baseline study to inform conservation efforts

Mashkour N, Jones K, Kophamel S, Hipolito T, Ahasan S, Walker G, et al.

PLoS One, 2020;15(10):e0230760.
PMID: 33095793 DOI: 10.1371/journal.pone.0230760

The impact of a range of different threats has resulted in the listing of six out of seven sea turtle species on the IUCN Red List of endangered species. Disease risk analysis (DRA) tools are designed to provide objective, repeatable and documented assessment of the disease risks for a population and measures to reduce these risks through management options. To the best of our knowledge, DRAs have not previously been published for sea turtles, although disease is reported to contribute to sea turtle population decline. Here, a comprehensive list of health hazards is provided for all seven species of sea turtles. The possible risk these hazards pose to the health of sea turtles were assessed and "One Health" aspects of interacting with sea turtles were also investigated. The risk assessment was undertaken in collaboration with more than 30 experts in the field including veterinarians, microbiologists, social scientists, epidemiologists and stakeholders, in the form of two international workshops and one local workshop. The general finding of the DRA was the distinct lack of knowledge regarding a link between the presence of pathogens and diseases manifestation in sea turtles. A higher rate of disease in immunocompromised individuals was repeatedly reported and a possible link between immunosuppression and environmental contaminants as a result of anthropogenic influences was suggested. Society based conservation initiatives and as a result the cultural and social aspect of interacting with sea turtles appeared to need more attention and research. A risk management workshop was carried out to acquire the insights of local policy makers about management options for the risks relevant to Queensland and the options were evaluated considering their feasibility and effectiveness. The sea turtle DRA presented here, is a structured guide for future risk assessments to be used in specific scenarios such as translocation and head-starting programs.

Matched MeSH terms: Immunosuppression
Fulltext Mesenchymal stem cells: a modern tool for immunomodulation

Rajesh Ramasamy

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):13-13.
MyJurnal

Immunomodulation is essential for controlling the immune system to maintain efficient immune surveillance and inflammation. Both arms of immunomodulation, namely immunostimulation and immunosuppression, are equally crucial in setting the optimal balance of immune response. However, diseases or conditions such as autoimmune diseases, tissue rejection due to transplantation and chronic inflammation require downregulation of overwhelming immune reactions. The conventional immunosuppressive drugs prevent the activation of immune cells, yet create an unsafe condition with toxic adverse effects. In such predicament, mesenchymal stem cells (MSCs) emerged as one of the safe immunosuppressive regiments and widely tested in clinical trials for numerous chronic inflammatory dis-eases. Mesenchymal stem cells are the origin of the stromal/mesenchymal cells in almost all solid organs, including the pulp of the tooth. In addition to providing structural support to the organ, MSCs participate in the tissue repair and regeneration by ameliorating an overly activated immune response locally and systemically. Regardless of the source, MSCs profoundly suppress the proliferation and effector functions of both innate and adaptive immune cells. The mechanism of inhibition primarily took place in the early phase of cell cycle and mediated via suppression of mainstream signalling pathways that involve cyclins and other cell cycle proteins. The antiproliferative activity of MSCs is not only limited to the healthy immune cells but extends to the various tumour cells of the immune system. Similarly, an array of cell signalling pathways that executed by cell cycle proteins found downregulated in the pres-ence of MSCs. The immunosuppressive activity exerted by MSCs is not specific to particular immune cells where it impairs a group of the common cell signalling pathways or putative cell cycle proteins which are vital elements for the proliferation.

Matched MeSH terms: Immunosuppression
Fulltext Unresolved pneumonia: a case report of Strongyloides stercoralis hyperinfection in an immunocompromised patient

Esteban Chin, Lim Han Hua

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):58-58.
MyJurnal

Introduction: Strongyloidiasis is endemic in the tropical and subtropical regions. Clinical manifestations of the dis-ease can range from asymptomatic eosinophilia in an immunocompetent host to a wide range of presentations in immunocompromised patients. Failure to consider the diagnosis of strongyloides infection, especially Strongyloides hyperinfection syndrome, is a major contributor of high mortality rate in such cases. Case Description: We report a case of 60 years old gentleman who was admitted to Sarawak General Hospital for a left subtrochanteric femur pathological fracture and the diagnosis of multiple myeloma was made in the same setting. He was started on treat-ment for multiple myeloma which includes high dose steroids. During his course of admission, he was diagnosed with hospital-acquired pneumonia was subsequently initiated with broad-spectrum antibiotics. Despite being exten-sively treated with multiple courses of broad-spectrum antibiotics, he deteriorated clinically, with eventual respirato-ry failure requiring ventilator support and ICU admission. A diagnosis of strongyloides hyperinfection syndrome was made after an incidental discovery of larvae in his sputum, which was later confirmed with stool sample. He was given a one-week course of albendazole 400mg twice daily and clinical improvement was observed. A repeated stool sample also demonstrated clearance of the parasites. Conclusion: This case highlights the need for clinical sus-picion of strongyloides hyperinfection syndrome in cases of unresolved pneumonia, especially for patients with risk factors of underlying immune-deficiency state. Preventive steps such early detection and eradication of strongyloides infection should be undertaken prior to initiation of immuno-suppressive therapy.

Matched MeSH terms: Immunosuppression
Fulltext Strongyloides Hyperinfection Syndrome in an Immunosuppressed Patient

Cheo, Seng Wee, Tan, Yee Ann, Low, Qin Jian

Borneo Journal of Medical Sciences, 2019;13(1):39-43.
MyJurnal

Strongyloides stercoralis is an intestinal nematode which is endemic in tropical and subtropical countries. The global prevalence of Strongyloides is unknown. Strongyloidiasis is found more frequently in the socioeconomically disadvantaged, in institutionalized populations, and in rural areas. The spectrum of disease varies. It may cause asymptomatic infection, mild eosinophilia or hyperinfection syndrome in the most severe form. Here we reported a case of Strongyloides hyperinfection syndrome in an immunosuppressed patient. This patient is a 54-year-old man with myasthenia gravis on long term azathioprine and prednisolone. He presented with fever associated with diarrhoea and was in septic shock. His blood culture was positive forKlebsiella pneumoniae.Strongyloides stercoralis larvae were detected in his sputum and stool sample. He was diagnosed to have Strongyloides hyperinfection and was treated with subcutaneous ivermectin. He recovered well. Our case demonstrated the association of Strongyloideshyperinfection with superimposed gram-negative sepsis as a consequence of prolonged immunosuppression. A high index of suspicion is needed in approaching patient with risk factors of hyperinfection syndrome.

Matched MeSH terms: Immunosuppression
Fulltext The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review

Ahmad S, Azid NA, Boer JC, Lim J, Chen X, Plebanski M, et al.

Front Immunol, 2018;9:2572.
PMID: 30473698 DOI: 10.3389/fimmu.2018.02572

Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine, which is thought to play a major role in the pathogenesis of inflammatory diseases, including allergy. TNF is produced at the early stage of allergen sensitization, and then continues to promote the inflammation cascade in the effector phase of allergic reactions. Consequently, anti-TNF treatment has been proposed as a potential therapeutic option. However, recent studies reveal anti-intuitive effects of TNF in the activation and proliferative expansion of immunosuppressive Tregs, tolerogenic DCs and MDSCs. This immunosuppressive effect of TNF is mediated by TNFR2, which is preferentially expressed by immunosuppressive cells. These findings redefine the role of TNF in allergic reaction, and suggest that targeting TNF-TNFR2 interaction itself may represent a novel strategy in the treatment of allergy.

Matched MeSH terms: Immunosuppression/methods
Fulltext Fatal infections in older patients with inflammatory bowel disease on anti-tumor necrosis factor therapy

Lee WS, Azmi N, Ng RT, Ong SY, Ponnampalavanar SS, Mahadeva S, et al.

Intest Res, 2017 Oct;15(4):524-528.
PMID: 29142521 DOI: 10.5217/ir.2017.15.4.524

Anti-tumor necrosis factor (anti-TNF) is highly effective in inflammatory bowel disease (IBD); however, it is associated with an increased risk of infections, particularly in older adults. We reviewed 349 patients with IBD, who were observed over a 12-month period, 74 of whom had received anti-TNF therapy (71 patients were aged <60 years and 3 were aged ≥60 years). All the 3 older patients developed serious infectious complications after receiving anti-TNFs, although all of them were also on concomitant immunosuppressive therapy. One patient developed disseminated tuberculosis, another patient developed cholera diarrhea followed by nosocomial pneumonia, while the third patient developed multiple opportunistic infections (Pneumocystis pneumonia, cryptococcal septicemia and meningitis, Klebsiella septicemia). All 3 patients died within 1 year from the onset of the infection(s). We recommend that anti-TNF, especially when combined with other immunosuppressive therapy, should be used with extreme caution in older adult patients with IBD.

Matched MeSH terms: Immunosuppression
Phytosterols isolated from Clinacanthus nutans induce immunosuppressive activity in murine cells

Le CF, Kailaivasan TH, Chow SC, Abdullah Z, Ling SK, Fang CM

Int Immunopharmacol, 2017 Mar;44:203-210.
PMID: 28119186 DOI: 10.1016/j.intimp.2017.01.013

Clinacanthus nutans (Burm. f.) Lindau is a traditional medicinal plant belonging to the Acanthaceae family. Its therapeutic potentials have been increasingly documented particularly the antiviral activity against Herpes Simplex Virus (HSV), anti-cancer, anti-oxidant, anti-inflammatory and immunomodulatory activities. However, majority of these studies used crude or fractionated extracts and not much is known about individual compounds from these extracts and their biological activities. In the present study, we have isolated four compounds (CN1, CN2, CN3 and CN4) from the hexane fractions of C. nutans leaves. Using NMR spectroscopic analysis, these compounds were identified to be shaftoside (CN1), stigmasterol (CN2), β-sitosterol (CN3) and a triterpenoid lupeol (CN4). To determine the immunosuppressive potential of these compounds, their effects on mitogens induced T and B lymphocyte proliferation and the secretion of helper T cell cytokines were examined. Among the four compounds, stigmasterol (CN2) and β-sitosterol (CN3) were shown to readily inhibit T cell proliferation mediated by Concanavalin A (ConA). However, only β-sitosterol (CN3) and not stigmasterol (CN2) blocks the secretion of T helper 2 (Th2) cytokines (IL-4 and IL-10). Both compounds have no effect on the secretion of Th1 cytokines (IL-2 and IFN-γ), suggesting that β-sitosterol treatment selectively suppresses Th2 activity and promotes a Th1 bias. CN3 was also found to significantly reduce the proliferation of both T helper cells (CD4(+)CD25(+)) and cytotoxic T cells (CD8(+)CD25(+)) following T cell activation induced by ConA. These results suggested that phytosterols isolated from C. nutans possess immunomodulatory effects with potential development as immunotherapeutics.

Matched MeSH terms: Immunosuppression
Fulltext Ectopic ACTH syndrome - Experience with Etomidate

Tong CV, Hussein Z

J ASEAN Fed Endocr Soc, 2017;32(1):54-56.
PMID: 33442086 DOI: 10.15605/jafes.032.01.10

For ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), when surgery is not feasible, or in cases of severe biochemical disturbances, immunosuppression or mental instability, medical therapy with agents such as etomidate is indicated. We present our experience in using etomidate for a 41-year old female with EAS secondary to a malignant mediastinal paraganglioma. We were able to demonstrate that etomidate can be used effectively to control severe hypercortisolism in a lower dose than previously described.

Matched MeSH terms: Immunosuppression
Fulltext Variable outcome in infantile-onset inflammatory bowel disease in an Asian cohort

Lee WS, Ng RT, Chan KW, Lau YL

World J Gastroenterol, 2016 Dec 28;22(48):10653-10662.
PMID: 28082818 DOI: 10.3748/wjg.v22.i48.10653

AIM: Infantile-onset inflammatory bowel disease (IO-IBD) with the onset of disease before 12 mo of age, is a different disease entity from childhood IBD. We aimed to describe the clinical features, outcome and role of mutation in interleukin-10 (IL-10) and interleukin-10 receptors (IL-10R) in Asian children with IO-IBD.
METHODS: All cases of IO-IBD, defined as onset of disease before 12 mo of age, seen at University Malaya Medical Center, Malaysia were reviewed. We performed mutational analysis for IL10 and IL10R genes in patients with presenting clinical features of Crohn's disease (CD).
RESULTS: Six [13%; CD = 3, ulcerative colitis (UC) = 2, IBD-unclassified (IBD-U) = 1] of the 48 children (CD = 25; UC = 23) with IBD have IO-IBD. At final review [median (range) duration of follow-up: 6.5 (3.0-20) years], three patients were in remission without immunosuppression [one each for post-colostomy (IBD-U), after standard immunosuppression (CD), and after total colectomy (UC)]. Three patients were on immunosuppression: one (UC) was in remission while two (both CD) had persistent disease. As compared with later-onset disease, IO-IBD were more likely to present with bloody diarrhea (100% vs 55%, P = 0.039) but were similar in terms of an associated autoimmune liver disease (0% vs 19%, P = 0.31), requiring biologics therapy (50% vs 36%, P = 0.40), surgery (50% vs 29%, P = 0.27), or achieving remission (50% vs 64%, P = 0.40). No mutations in either IL10 or IL10R in the three patients with CD and the only patient with IBD-U were identified.
CONCLUSION: The clinical features of IO-IBD in this Asian cohort of children who were negative for IL-10 or IL-10R mutations were variable. As compared to childhood IBD with onset of disease after 12 mo of age, IO-IBD achieved remission at a similar rate.

Matched MeSH terms: Immunosuppression
Early infection with Marek's disease virus can jeopardize protection conferred by laryngotracheitis vaccines: a method to study MDV-induced immunosuppression

Faiz NM, Cortes AL, Guy JS, Fletcher OJ, West M, Montiel E, et al.

Avian Pathol, 2016 Dec;45(6):606-615.
PMID: 27207594

Marek's disease virus (MDV) is a herpesvirus that induces lymphomas and immunosuppression in chickens. MDV-induced immunosuppression (MDV-IS) is divided into two phases: early-MDV-IS occurring mainly in chickens lacking maternal antibodies (MAb) against MDV and associated with lymphoid organ atrophy; and late-MDV-IS occurring once MDV enters latency and during tumour development. Our objectives were to document the impact of late-MDV-IS on commercial poultry (meat-type chickens bearing MAb against MDV and that were vaccinated or unvaccinated against MD) and to optimize a model to study late-MDV-IS under laboratory conditions. The impact of late-MDV-IS was evaluated by assessing the effect of early infection (day of age) with a very virulent plus MDV (vv+MDV) on the efficacy of chicken-embryo-origin (CEO) infectious laryngotracheitis (ILT) virus vaccine against ILT challenge. The CEO ILT vaccine was administered in water at 14 days of age and ILT virus (ILTV) challenge was done intratracheally at 30 days of age. Development of ILT was monitored by daily evaluation of clinical signs, development of gross and histological lesions in trachea, and quantification of ILTV transcripts in trachea. Infection with vv+MDV strain 648A resulted in total abrogation of protection conferred by the CEO vaccine against ILTV challenge even in chickens vaccinated at 1 day of age with either HVT, HVT+SB-1, or CVI988. Chickens exposed to vv+MDV prior to vaccination with CEO ILTV vaccine had similar (P

Matched MeSH terms: Immunosuppression
Fulltext When dermatomyositis patient has blurring of vision - what goes wrong?

Ng CWK, Hanizasurana H, Nor Azita AT, Nor Fariza N, Zabri K

Medicine & Health, 2016;11(2):313-318.
MyJurnal

Cytomegalovirus (CMV) retinitis occurs predominantly in Human Immunodeficiency Virus (HIV) -infected patients. It was also reported in HIV-seronegative patients with systemic autoimmune disorder requiring systemic immunosuppression, organ or bone marrow transplantation, haematological or breast malignancy receiving chemotherapy, ocular diseases following intraocular or periocular corticosteroid injection, diabetes mellitus and Good syndrome. However, CMV retinitis in patients with concurrent dermatomyositis and malignancy has not been previously reported. It has not been reported in cancer other than haematological or breast malignancy, or in cancer patient prior to chemotherapy. We report a case of 40-year-old HIV-seronegative woman with underlying dermatomyositis and lung malignancy who developed right CMV retinitis which relapsed after recommencement of immunosuppressant. Both episodes of CMV retinitis were successfully treated after taken her immunocompromised state into consideration.

Matched MeSH terms: Immunosuppression
Cryopreservation of Human Mesenchymal Stem Cells for Clinical Applications: Current Methods and Challenges

Yong KW, Wan Safwani WK, Xu F, Wan Abas WA, Choi JR, Pingguan-Murphy B

Biopreserv Biobank, 2015 Aug;13(4):231-9.
PMID: 26280501 DOI: 10.1089/bio.2014.0104

Mesenchymal stem cells (MSCs) hold many advantages over embryonic stem cells (ESCs) and other somatic cells in clinical applications. MSCs are multipotent cells with strong immunosuppressive properties. They can be harvested from various locations in the human body (e.g., bone marrow and adipose tissues). Cryopreservation represents an efficient method for the preservation and pooling of MSCs, to obtain the cell counts required for clinical applications, such as cell-based therapies and regenerative medicine. Upon cryopreservation, it is important to preserve MSCs functional properties including immunomodulatory properties and multilineage differentiation ability. Further, a biosafety evaluation of cryopreserved MSCs is essential prior to their clinical applications. However, the existing cryopreservation methods for MSCs are associated with notable limitations, leading to a need for new or improved methods to be established for a more efficient application of cryopreserved MSCs in stem cell-based therapies. We review the important parameters for cryopreservation of MSCs and the existing cryopreservation methods for MSCs. Further, we also discuss the challenges to be addressed in order to preserve MSCs effectively for clinical applications.

Matched MeSH terms: Immunosuppression

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