Current immunosuppressants have nonspecific immuosuppressive effects, and are not helpful for tolerance induction. Consequently, transplant patients cannot discontinue using them, and their nonspecific immunosuppressive effects result in many side effects, including infection and malignancy. However, most of cellular immunotherapy can have donor antigen-specific immunsuppressive effects. Therefore, cell therapy could be an alternative or adjunctive to nonspecific immunosuppressants. Polyclonal or antigen-specific Foxp3+ regulatory T cells have been actively tried for prevention of acute rejection, treatment of chronic rejection, or tolerance induction in clinical trials. Regulatory macrophages are also under clinical trials for kidney transplant patients. IL-10-secreting type 1 regulatory T cells and donor- or recipient-derived tolerogenic dendritic cells will also be used for immunoregulation in clinical trials of kidney transplantation. These cells have antigen-specific immunoregulatory effects. Mesenchymal stromal cells (MSCs) have good proliferative capacity and immunosuppressive actions independently of major histocompatibility complex; therefore, even third-party MSCs can be stored and used for many patients. Cell therapy using various immunoregulatory cells is now promising for not only reducing side effects of nonspecific immunosuppressants but also induction of immune tolerance, and is expected to contribute to better outcomes in transplant patients.
Cell- and Tissue-Based Therapy* ; Dendritic Cells ; Humans ; Immune Tolerance ; Immunosuppressive Agents ; Immunotherapy ; Kidney ; Kidney Transplantation* ; Macrophages ; Major Histocompatibility Complex ; Mesenchymal Stromal Cells ; T-Lymphocytes, Regulatory ; Tissue Donors

Long-term survivors in renal transplantation have been increasing, as medical care has improved in addition to development of new immunosuppressants. Therefore, cardiovascular disease, especially ischemic heart disease and chronic allograft dysfunction have become main obstacles to longer survival and better quality of life. Dyslipidemia, which is a well-known risk factor of ischemic heart disease in general population, is more common in renal transplantation patients. Moreover, dyslipidemia is suggested as a nonimmunological risk factor of chronic allograft dysfunction. Therefore, it is important to manage dyslipidemia properly to improve patient and graft survival in renal transplantation. But, specific approach, tailored to renal transplant patients is necessary in the treatment of dyslipidemia, because there are significant differences between renal transplantation patients and general population. We present here, epidemiology, mechanism, and impact of dyslipidemia on ischemic heart disease and chronic allograft dysfunction, and overall approach to dyslipidemia in renal transplantation patients, including treatment guideline.
Allografts ; Cardiovascular Diseases ; Dyslipidemias* ; Epidemiology ; Graft Survival ; Humans ; Immunosuppressive Agents ; Kidney Transplantation ; Myocardial Ischemia ; Quality of Life ; Risk Factors ; Survivors

Macrophage accumulation has been recognized as a feature of allograft rejection, however, the role of macrophages in rejection remains underappreciated. Macrophages are present within graft tissues throughout the lifespan of the graft, including acute rejection episodes. Recent advances in macrophage biology have demonstrated that different types of macrophages in grafts serve a range of functions, including promotion or attenuation of inflammation, participation in innate and adaptive immune responses, and mediation of tissue injury, fibrosis, and tissue repair. Macrophages contribute to both the innate and acquired arms of the alloimmune response, and, thus, may be involved in all aspects of acute and chronic allograft rejection. Macrophages are also involved in hyperacute and acute vascular rejection of xenografts. A deeper understanding of how macrophages accumulate within grafts and of the factors that control differentiation and function of these cells could lead to identification of novel therapeutic targets in transplantation.
Arm ; Biology ; Fibrosis ; Graft Rejection ; Inflammation ; Macrophages ; Negotiating ; Rejection (Psychology) ; Transplantation, Heterologous ; Transplantation, Homologous ; Transplants

No abstract available.
Kidney ; Kidney Transplantation

Regulatory T cells (Treg) naturally rein in immune attacks, and they can inhibit rejection of transplanted organs and even reverse the progression of autoimmune diseases in mice. The initial safety trials of Treg against graft-versus-host disease (GVHD) provided evidence that the adoptive transfer of Treg is safe and capable of limiting disease progression. Supported by such evidence, numerous clinical trials have been actively investigating the efficacy of Treg targeting autoimmune diseases, type I diabetes, and organ transplant rejection, including kidney and liver. The limited quantity of Treg cells harvested from peripheral blood and subsequent in vitro culture have posed a great challenge to large-scale clinical application of Treg; nevertheless, the concept of CAR (chimeric antigen receptor)-Treg has emerged as a potential resolution to the problem. Recently, two CAR-T therapies, tisagenlecleucel and axicabtagene ciloleucel, were approved by the US FDA for the treatment of refractory or recurrent acute lymhoblastic leukemia. This approval could serve as a guideline for the production protocols for other genetically engineered T cells for clinical use as well. The phase I and II clinical trials of these agents has demonstrated that genetically engineered and antigen-targeting T cells are safe and efficacious in humans. In conclusion, both the promising results of Treg cell therapy from the clinical studies and the recent FDA approval of CAR-T therapies are paving the way for CAR-Treg therapy in clinical use.
Adoptive Transfer ; Animals ; Autoimmune Diseases ; Cell- and Tissue-Based Therapy* ; Disease Progression ; Graft vs Host Disease ; Humans ; In Vitro Techniques ; Kidney ; Leukemia ; Liver ; Mice ; T-Lymphocytes ; T-Lymphocytes, Regulatory* ; Transplantation ; Transplants

ABO-incompatible kidney transplantation (ABOi KT) was introduced to expand the donor pool and minimize shortage of kidneys for transplantation. Because improved outcomes of ABOi KT were reported in Japan in the early 2000s, the number of ABOi KTs has been increasing worldwide. In addition, a better understanding of immune pathogenesis and subsequent aggressive immunosuppression has helped to make effective desensitization protocols. Current strategies of ABOi KT consist of pretransplant antibody removal using plasmapheresis or immunoadsorption to prevent hyperacute rejection and potent maintenance immunosuppression, such as tacrolimus and mycophenolate mofetil, to inhibit antibody-mediated rejection. Recent outcomes of ABOi KT are comparable with ABO-compatible KT. However, there are still many problems to be resolved. Very high anti-ABO antibody producers are difficult to desensitize. In addition, ABOi KT is associated with an increased risk of infection and possibly malignancy due to aggressive immunosuppression. Optimization of desensitization and patient-tailored immunosuppression protocols are needed to achieve better outcomes of ABOi KT. This review provides an overview of the history, immune mechanism, immunosuppressive protocol, outcomes, current obstacles, and future perspectives in ABOi KT.
Blood Group Incompatibility ; Humans ; Immunosuppression ; Japan ; Kidney Transplantation* ; Kidney* ; Plasmapheresis ; Tacrolimus ; Tissue Donors

Cardiovascular disease (CVD) is the leading cause of death in renal allograft recipients with functioning graft. Our study aimed to determine the incidence and the risk factors of cardiovascular disease after renal transplantation in Korea. We retrospectively analyzed 430 adult recipients who underwent kidney transplantation between January 1997 and February 2007. CVD was defined as a composite outcome of ischemic heart disease, cerebrovascular accident and peripheral vascular disease. Mean age of recipients was 40.0+/-11.8 yr. Mean duration of follow-up was 72+/-39 months. The cumulative incidence of CVD after renal transplantation was 2.4% at 5 yr, 5.4% at 10 yr and 11.4% at 12 yr. Multivariate analysis revealed that recipient's age, diabetes mellitus and duration of dialysis before transplantation were associated with post-transplant CVD (hazard ratio 1.843 [95% CI, 1.005-3.381], 3.846 [95% CI, 1.025-14.432] and 3.394 [95% CI, 1.728-6.665] respectively). In conclusion, old age, duration of dialysis and diabetes mellitus are important risk factors for post-transplant CVD, although the incidence of post-renal transplant CVD is lower in Korea than that in western countries.
Adult ; Age Factors ; Cardiovascular Diseases/*epidemiology/etiology ; Diabetes Complications ; Female ; Humans ; Incidence ; *Kidney Transplantation ; Male ; Middle Aged ; Multivariate Analysis ; Renal Dialysis ; Republic of Korea ; Retrospective Studies ; Risk Factors

BACKGROUND: Hepatitis B virus (HBV)-associated glomerulonephritis (HBGN) occurs with high prevalence in Asia, and accounts for over 30% of secondary glomerulonephritis in Korea. However, the association between HLA and HBGN has been hardly reported upon in the literature. METHODS: A total of 50 Korean patients with HBGN, 100 HBsAg (-) healthy controls and 89 HBsAg (+) controls (subjects with chronic HBV infection, HBsAg positive at least for 6 months) were included. HLA-DR typing was done using a reverse sequence specific oligonucleotide typing kit and HLA-DRB1 genotyping was done for HLA-DR2 positive samples by PCR-single strand conformational polymorphism method. RESULTS: In the HBGN patients, HLA-DR2 was highly significantly increased compared with HBsAg (-) controls (p=0.0002, corrected p=0.002, OR=4.0) and also compared with HBsAg (+) controls (p= 0.0005, corrected p=0.006, OR=3.7). Different HLA- DR2 alleles were strongly associated with different pathologic subtypes of HBGN: DRB1*1502 was associated with membranoproliferative glomerulonephritis (MPGN) (p=0.0003, corrected p=0.004, OR=14.5), and DRB1*1501 with membranous nephropathy (MN) (p= 0.05, OR=3.8). These associations were also found to be significant compared with HBsAg (+) controls (HBV-MPGN, p=0.002; HBV-MN, p=0.04). DR13 was found to have some protective effect in HBV infection (p=0.01, OR=0.3) and DR11 was found to be weakly associated with HBV infection (p=0.01, OR= 4.6), however these HLA alleles were not associated with disease susceptibility to HBGN. CONCLUSION: These results suggest that HLA- DR2 or a closely associated genetic factor is associated with disease susceptibility to HBGN, and different HLA-DR2 subtypes are associated with different pathologic subtypes of HBGN in Koreans.
Alleles ; Asia ; Disease Susceptibility ; Fibrinogen ; Glomerulonephritis* ; Glomerulonephritis, Membranoproliferative ; Glomerulonephritis, Membranous ; Hepatitis B Surface Antigens ; Hepatitis B virus ; Hepatitis B* ; Hepatitis* ; HLA-DR Antigens* ; HLA-DR2 Antigen ; HLA-DRB1 Chains ; Humans ; Korea ; Prevalence

Chronic renal allograft dysfunction (CRAD) has been the rnost frequent cause of graft failure for last decade. Even in cycloporine era the incidence of CRAD has not changed. From Jan 1992 to Dec 1994 118 kidney transplants performed in Seoul National University Hospital had been entered into our database. All patients had been followed for at least 1 year. CRAD is defined if there had been progressive deterioration of renal function that was not explained by other causes and finally serum creatinine (Scr) had doubled from basal Scr after transplantation and has been maintained. Analyzed factors as follows; HLA misrnatch, living or cadaver transplant, ABO mismatch, acute rejecton (AR), frequency and timing of AR, donor age, recipient age, cold ischmic time, delayed graft function, proteinuria, infection. A CRAD has developed in 27 (23%) patients. The incidence of CRAD with time was analyzed by Kaplan-Meier survival analysis and compared with log-rank test. We concluded that in univariate anlaysis the risk factors are acute rejection, frequency of AR, AR after 3 months after tranplantation, age of recipient<15 and cold ischmic time> 40rnin for living transplants. Although HLAMM=0 significantly decreased the risk of CRAD (P<0.05), there was no difference in renal survival between groups of HLAMM>1. AR and HLAMM (HLAMM=O vs. HLAMM>1) were related each other (P=0.02).
Allografts* ; Cadaver ; Creatinine ; Delayed Graft Function ; Humans ; Incidence ; Kidney ; Kidney Transplantation ; Proteinuria ; Risk Factors* ; Seoul ; Tissue Donors ; Transplants

BACKGROUND: Although a growing number of guidelines and clinical researches are available for immunosuppressive treatment of post-transplantation, there is no clinical practice guideline for the care of kidney transplant recipients in Korea. Selection of a researchable question is the most important step in conducting qualified guideline development. Thus, we aimed to formulate key questions for Korean guideline to aid clinical decision-making for immunosuppressive treatment. METHODS: Based on previous published guidelines review, a first survey was constructed with 29 questions in the range of immunosuppressive treatments. The experts were asked to rate the clinical importance of the question using a 5-point Likert scale. The questions reached 60% or more from the first survey and additional new questions were included in the second survey. In analyzing the responses to items rated on the 9-point scale, consensus agreement on each question was defined as 75% or more of experts rating 7 to 9. RESULTS: In the first survey, 50 experts were included. Among the 29 questions, 27 were derived to get 60% or more importance and 3 new questions were additionally identified. Through the second survey, 9 questions were selected that experts reached consensus on 75% and over of the options. Finally, we developed key questions using PICO (patient, intervention, comparison, and outcome) methodology. CONCLUSION: The experts reached a high level of consensus on many of key questions in the survey. Final key questions provide direction for developing clinical practice guideline in the immunosuppressive treatment of transplantation.
Clinical Decision-Making ; Consensus ; Kidney Transplantation ; Kidney ; Korea ; Transplant Recipients