Reduction in proteinuria after immunosuppress-sive therapy and long-term kidney outcomes in patients with immunoglobulin A nephropathy

( Shin Chan Kang ),( Hyung Woo Kim ),( Tae Ik Chang ),( Ea Wha Kang ),( Beom Jin Lim ),( Jung Tak Park ),( Tae-hyun Yoo ),( Hyeon Joo Jeong ),( Shin-wook Kang ),( Seung Hyeok Han ) 대한내과학회 2021 The Korean Journal of Internal Medicine Vol.36 No.5

Background/Aims: Despite controversy regarding the benefits of immunosuppressive therapy in immunoglobulin A nephropathy (IgAN), clinical outcomes may vary depending on the patient’s responsiveness to this therapy. This study evaluated long-term kidney outcomes according to the extent of proteinuria reduction after immunosuppression in IgAN patients. Methods: Among 927 patients with biopsy-proven IgAN, 127 patients underwent immunosuppression. Time-averaged urine protein-creatinine ratio before and within 1 year after start of immunosuppression were calculated, and responsiveness to immunosuppression was assessed as the reduction of proteinuria between the two periods. Patients were classified into tertiles according to the extent of proteinuria reduction. We compared the slopes of estimated glomerular filtration rate (eGFR) decline using a linear mixed model, and estimated hazard ratios (HRs) for disease progression (defined as development of a ≥ 30% decline in eGFR or end-stage renal disease) using a Cox proportional hazard model. Results: Median extent of proteinuria reduction was -2.1, -0.9, and -0.2 g/gCr in the first, second, and third tertiles, respectively. There were concomitant changes in the slopes of annual eGFR decline: -2.03, -2.44, and -4.62 mL/min/1.73 ㎡ among the first, second, and third tertiles, respectively. In multivariable Cox analysis, the HRs (95% confidence intervals) for disease progression were 0.30 (0.12 to 0.74) in the first tertile and 0.70 (0.34 to 1.45) in the second tertile compared with the thirdtertile. Conclusions: This study showed that greater proteinuria reduction after immunosuppression was associated with a lower risk of disease progression in patients with IgAN, suggesting that responsiveness to immunosuppression may be an important determinant of kidney outcomes.

Galectin-9 is Involved in Immunosuppression Mediated by Human Bone Marrow-derived Clonal Mesenchymal Stem Cells

김시나,이현주,전명신,이택기,송순욱 대한면역학회 2015 Immune Network Vol.15 No.5

Bone marrow-derived mesenchymal stem cells (MSCs) have immunomodulatory properties and can suppress exaggerated pro-inflammatory immune responses. Although the exact mechanisms remain unclear, a variety of soluble factors are known to contribute to MSC-mediated immunosuppression. However, functional redundancy in the immunosuppressive properties of MSCs indicates that other uncharacterized factors could be involved. Galectin-9, a member of the β-galactoside binding galectin family, has emerged as an important regulator of innate and adaptive immunity. We examined whether galectin-9 contributes to MSC-mediated immunosuppression. Galectin-9 was strongly induced and secreted from human MSCs upon stimulation with pro-inflammatory cytokines. An in vitro immunosuppression assay using a knockdown approach revealed that galectin-9-deficient MSCs do not exert immunosuppressive activity. We also provided evidence that galectin-9 may contribute to MSC-mediated immunosuppression by binding to its receptor, TIM-3, expressed on activated lymphocytes, leading to apoptotic cell death of activated lymphocytes. Taken together, our findings demonstrate that galectin-9 is involved in MSC-mediated immunosuppression and represents a potential therapeutic factor for the treatment of inflammatory diseases.

소아 신장이식 환자에서의 면역억제요법

민상일,한아람,최찬중,김송이,강희경,하일수,하종원 대한이식학회 2015 Korean Journal of Transplantation Vol.29 No.1

Over the last two decades, newer immunosuppressive agents have been introduced in the field of solid organ transplantation, and provided better graft and patient outcome. A wider range of immunosuppressants available to transplant physicians have resulted in improved therapeutic strategies to offer the combinations of medications with non-overlapping toxicities and more suitable immunosuppression. However, only a few clinical trials of new immunosuppressants have been conducted in pediatric patients. This review will discuss the cutting-edge strategy of immunosuppression in children and the current status of new immunosuppressive agents in pre- and post-transplant management to prevent kidney allograft rejection. 1954년 성공적인 신장이식 이후, 말기신부전이 있는 환자에서 신장이식은 환자의 생존율을 유지하고 삶의 질을향상시키는 최적의 치료로 인식되고 있다(1). 소아 환자에서는 과거에 수술 술기, 면역학적 문제 등으로 인해 성인과같은 좋은 이식편 및 환자 생존율을 기대할 수 없었으나최근 이십여 년 동안 다양한 면역억제제의 개발과 사용 방법의 향상으로 인해 소아 신장이식 환자에서도 이식편 및환자 생존율을 향상시켜왔다(2). 많은 종류의 면역억제제의 개발은 다양한 조합의 면역억제 치료를 가능하게 하였고 이는 각각 약물의 용량을 낮춤으로써 독성의 발생을 줄이면서도 환자 및 이식편의 생존율을 향상시키는 결과를가져왔다(3). 그러나 소아에서는 면역억제제의 사용에 있어 성인과 달리 고려할만한 몇 가지 쟁점이 있다. 첫째, 새로운 면역억제제를 사용하기 전에 성인에서는 필수적으로시행하는 무작위배정임상시험이 소아 환자에서 시행되는경우는 흔하지 않아 안전성 및 유효성에 대한 근거가 다양하지 않으며 일부 시행된 임상 시험도 주로 서양의 소아환자를 대상으로 한 연구로서 우리나라 환자들에 그대로적용하기가 어려운 점이 있다. 둘째, 소아 연령에서는 각면역억제제의 약동학 및 약역학 연구가 흔하지 않으며 나이에 따라 약동학이 다양하다. 셋째, 소아는 면역체계 역시발달하고 있는 상태이므로 성인과 다른 감염의 위험성이존재한다. 넷째, 장기적인 면역억제치료가 필수적이므로이에 따르는 다양한 문제들을 내포하게 된다(4). 따라서 저자들은 소아 신장이식 환자에서의 면역억제 치료의 현황과 중요 면역억제제의 고려 사항 등을 다루고자 한다.

면역억제제 Basiliximab이 신장이식 1년 이내 급성 거부반응의 빈도에 미치는 영향

홍우성(Woo Sung Hong),이병모(Byung Mo Lee),오창권(Chang-Kwon Oh),김세중(Se Joong Kim),김흥수(Heungsoo Kim),신규태(Gyu Tae Shin) 대한외과학회 2007 Annals of Surgical Treatment and Research(ASRT) Vol.73 No.6

Purpose: Basiliximab has become widely used in clinical practice for initial immunosuppression in renal transplantation cases, to reduce the incidence of acute rejection without adverse events. Herein, we report the early outcomes of renal transplantation using basiliximab at a single center. Methods: This retrospective study included 148 renal allograft recipients at a single center. All patients were followed for longer than 1 year after transplantation, and treated with a calcineurin inhibitor and steroids for maintenance immunosuppression. The use of basiliximab and mycophenolate mofetil (MMF) was optional. We compared the incidence of episodes of acute graft rejection in kidney recipients who were treated with basiliximab as an initial immunosuppressive therapy with those who were treated without basiliximab. Results: Basiliximab was used for initial immunosuppression in 58 patients. Patients maintained immunosuppression with triple (n=69) or double (n=79) regimens including a calcineurin inhibitor (cyclosporine A (n=111) or tacrolimus (n=37)) and methylprednisolone with or without MMF. Thirty-six (24.3%) patients had a rejection episode within 1 year after transplantation and twenty-six (17.6%) patients had an episode of infection. The patients who were treated with basiliximab had fewer rejection episodes (n=11, 18.9%) within the first year after transplantation than the patients who did not take basiliximab (n=25, 27.7%); this difference was not statistically significant. (P=0.245). However, basiliximab significantly affected the number of rejection episodes in the double regi men group (P=0.006), but not the number of rejections in the triple regimen group (P=0.432) and did not affect the number of infection episodes in both groups (P value of double, triple=0.291, 0.772) within one year after transplantation. Conclusion: The results of this study suggest that basiliximab might be more useful for graft recipients who are treated with double immunosuppression with a calcineurin inhibitor and steroid than for the recipients with triple immunosuppression including MMF.

Prevention of Hepatitis B reactivation in the setting of immunosuppression

( Venessa Pattullo ) 대한간학회 2016 Clinical and Molecular Hepatology(대한간학회지) Vol.22 No.2

Advances in the treatment of malignant and inflammatory diseases have developed over time, with increasing use of chemotherapeutic and immunosuppressive agents of a range of drug classes with varying mechanism and potency in their effects on the immune system. These advances have been met with the challenge of increased risk of hepatitis B virus (HBV) reactivation in susceptible individuals. The magnitude of risk of HBV reactivation is associated with the individual’s HBV serological status and the potency and duration of immunosuppression. Individuals with chronic hepatitis B (CHB) and previously infected but serologically cleared HBV infection are both susceptible to HBV reactivation. HBV reactivation in the setting of immunosuppression is a potentially life threatening condition leading to liver failure and death in extreme cases. It is important to recognize that HBV reactivation in the setting of immunosuppression is potentially preventable. Therefore, identification of patients at risk of HBV reactivation and institution of prophylactic antiviral therapy prior to initiation of immunosuppression is essential. (Clin Mol Hepatol 2016;22:219-237)

항암제 (5-fluorouracil, doxorubicin, vincristine)로 인한 비장세포의 면역억제에 대한 Bordetella bronchiseptica의 보호 효과

이유정,주홍구,Lee, You-Jeong,Joo, Hong-Gu 대한수의학회 2022 大韓獸醫學會誌 Vol.62 No.3

5-Fluorouracil, doxorubicin, and vincristine are chemotherapy agents used to treat various cancers, such as breast cancer and lymphoma for decades, and their effects on cancer have been proven. On the other hand, these anti-cancer drugs cause fatal side effects, including immunosuppression. This study investigated whether sonicated Bordetella bronchiseptica bacterin (B. bronchiseptica) can attenuate the immunosuppression of spleen cells induced by these chemotherapy agents and which subsets of spleen cells were affected. B. bronchiseptica increased the metabolic activity of spleen cells treated with 3 anti-cancer drugs. Cell death analysis using Annexin V/propidium iodide showed that B. bronchiseptica markedly decreased the death of spleen cells. The subsets of spleen cells were analyzed by flow cytometry using a surface marker-specific antibody. B. bronchiseptica increased nitric oxide production in the spleen cells treated with anti-cancer drugs (p < 0.0001). Despite the pharmacological effects of anti-cancer drugs, many patients suffer from the fatal side effects of immunosuppression. This study provides valuable information on how to overcome chemotherapy-induced immunosuppression.

Efficacy and Safety of a Steroid-Free Immunosuppressive Regimen after Liver Transplantation for Hepatocellular Carcinoma

Qiang Wei,Xiao Xu,Chao Wang,Runzhou Zhuang,Li Zhuang,Lin Zhou,Haiyang Xie,Jian Wu,Min Zhang,Yan Shen,Weilin Wang,Shusen Zheng 거트앤리버 소화기연관학회협의회 2016 Gut and Liver Vol.10 No.4

Background/Aims: We aimed to evaluate the efficacy and safety of an immunosuppressive regimen without steroids after liver transplantation (LT) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: Sixty-six HCC patients who underwent an immunosuppressive regimen without steroids after LT were enrolled in the steroid-free group. The preoperative characteristics and postoperative outcomes of these patients were compared with those of 132 HCC recipients who were placed on an immunosuppressive regimen using steroids (steroid group). The incidence of acute rejection, HBV recurrence, infection, and new-onset diabetes mellitus and the overall and tumor-free survival rates were compared between the two groups. Results: Differences were not observed in the 1-year (83.3% vs 97.0%, p=0.067), 3-year (65.4% vs 75.8%, p=0.067) or 5-year (56.3% vs 70.7%, p=0.067) patient survival rates or in the 1-year (62.1% vs 72.7%, p=0.067), 3-year (49.8% vs 63.6%, p=0.067) or 5-year (48.6% vs 63.6%, p=0.067) tumor-free survival rates between the two groups, respectively. In the steroid-free group, the patients who fulfilled the Milan criteria had higher overall and tumor-free survival rates than those in the steroid group (p<0.001). The prevalence of HBV recurrence (3.0% vs 13.6%, p=0.02) was significantly lower in the steroid-free group compared with the steroid group. Conclusions: After LT, an immunosuppressive regimen without steroids could be a safe and feasible treatment for HBVrelated HCC patients, thus resulting in the reduction of HBV recurrence. Based on the observed survival rates, patients who fulfill the Milan criteria may derive benefits from steroidfree immunosuppression.

Murine Mammary Carcinoma Induces Chronic Systemic Inflammation and Immunosuppression in BALB/c Mice

Dasha Fuentes,Alejandro Cabezas-Cruz,Circe Mesa,Tania Carmenate,Darel Martínez,Anet Valdés-Zayas,Enrique Montero,Rolando Pérez 한국유방암학회 2022 Journal of breast cancer Vol.25 No.3

Purpose: The F3II cell line is a highly invasive variant of mammary carcinoma. Although it is frequently used as a model to evaluate the efficacy of immunotherapy, its impact on the immune system remains poorly understood. The main objectives of this study were to evaluate the effects of F3II tumors on the development of chronic inflammation and to characterize tumor-associated immunosuppression. Methods: Following the experimental implantation of F3II tumors in BALB/c mice, alterations in the liver and spleen anatomy and the numbers of circulating leukocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells were measured using hematological techniques, histopathological analysis, and flow cytometry. The capacity of the F3II tumor-bearing mice to reject MB16F10 allogeneic tumor transplantation was also evaluated. In addition, the restoration of immune parameters in tumor-bearing mice was evaluated after standard breast cancer chemotherapy and surgical tumor excision. Results: F3II tumor implantation increased the levels of chronic inflammatory markers, such as the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios, and caused myeloid alterations, including extramedullary granulopoiesis and megakaryopoiesis, along with the recruitment of MDSCs to the spleen. Chemotherapy or surgical F3II tumor removal completely rescued the tumor-associated extramedullary granulopoiesis and megakaryopoiesis. Notably, the presence of F3II tumors reduced the capacity of BALB/c mice to reject MB16F10 allogeneic tumor transplantation. Conclusion: These results support the occurrence of F3II tumor-mediated immune cell dysfunction, which mimics the immune alterations characterized by chronic systemic inflammation and immunosuppression observed in breast cancer in clinical settings. Thus, the F3II tumor model is relevant for evaluating novel breast cancer immunotherapies and combinations in preclinical studies. This model could also be useful for identifying appropriate therapeutic targets and developing proof-of-concept experiments in the future.

면역 억제제 투여후 발생한 Kaposi 육종

양종규,김성욱,백승철,김정원,김석영 ( Jong Kyu Yang,Sung Wook Kim,Seung Churl Paik,Chung Won Kim,Suk Young Kim ) 대한피부과학회 1997 대한피부과학회지 Vol.35 No.3

Iatrogenically developed immunosuppression-associated Kaposis sarcoma is the result of immunosuppressive therapy after an organ transplantation, particularly after a renal transplantation. Since the advent of powerful immunosuppressive agents such as cyclosporine, recently the incidence of Kaposis sarcoma has been increased. In addition to immunosuppression, other factors, such as genetic predisposition, environmental and geographic factors, and oncogenic viruses, may play a role in the pathogenesis of this tumor. Ilerein we report a case of Keposis sarcoma with multiple organ involvement of the skin, lung, small intestine and mesenteric lymph node in a renal allograft recipient who received cyclosporine and prednisolone. Reduction of the dosage of immunosuppressant for 1 month resulted in improvement of the cutaneous lesions. (Kor J Dermatol 1997;35(3): 551-555)

면역억제자에서 만성 B형간염의 예방적 치료

윤아일린 대한소화기학회 2019 대한소화기학회지 Vol.74 No.5

Improved management of chronic hepatitis B patients with oral nucleos(t)ide analogues has increased the number of these patients who are getting older and have other accompanying comorbidities. These comorbidities frequently require various immunosuppression treatments and/or cytotoxic chemotherapy. Not only the patients who are positive for HBsAg, but also the patients who are positive for isolated anti-HBc are at risk for hepatitis B reactivation during immunosuppression. Prophylactic antiviral treatment with oral nucleos(t)ide analogues with high genetic barriers can decrease the risks of HBV reactivation, HBV reactivation- associated hepatitis, and mortality in these patients. It is crucial to screen HBV markers in all of the patients who have to undergo immunosuppression, be administered prophylactic antiviral treatment in the high risk groups, and be monitored for HBV reactivation during and after immunosuppression and/or cytotoxic chemotherapy. This study summarizes the recommendations from the recently updated guidelines from Korea, United States, and Europe.