Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the T cell part of the adaptive immune system is highlighted. Naïve T cell lymphopenia, in combination with the expansion of highly differentiated memory T cells, are the hallmarks of immunological ageing. The decreased production of newly formed T cells by the thymus is critically involved. This affects both the CD4 and CD8 T cell compartment and may contribute to the expansion of memory T cells. Th

Human Allogeneic Bone Marrow and Adipose Tissue Derived Mesenchymal Stromal Cells Induce CD8+ Cytotoxic T Cell Reactivity

INTRODUCTION: For clinical applications, Mesenchymal Stromal Cells (MSC) can be isolated from bone marrow and adipose tissue of autologous or allogeneic origin. Allogeneic cell usage has advantages but may harbor the risk of sensitization against foreign HLA. Therefore, we evaluated whether bone marrow and adipose tissue-derived MSC are capable of inducing HLA-specific alloreactivity. METHODS: MSC were isolated from healthy human Bone Marrow (BM-MSC) and adipose tissue (ASC) donors. Peripheral Blood Mononuclear Cells (PBMC) were co-cultured with HLA-AB mismatched BM-MSC or ASC precultured with or without IFNy. After isolation via FACS sorting, the educated CD8+ T effector populations were exposed for 4 hours to Europium labeled MSC of the same HLA make up as in the co-cultures or with different HLA. Lysis of MSC was determined by spectrophotometric measurement of Europium release. RESULTS: CD8+ T cells educated with BM-MSC were capable of HLA specific lysis of BM-MSC. The maximum lysis was 24% in an effector:target (E:T) ratio of 40:1. Exposure to IFNγ increased HLA-I expression on BM-MSC and increased lysis to 48%. Co-culturing of PBMC with IFNγ-stimulated BM-MSC further increased lysis to 76%. Surprisingly, lysis induced by ASC was significantly lower. CD8+ T cells educated with ASC induced a maximum lysis of 13% and CD8+ T cells educated with IFNγ-stimulated ASC of only 31%. CONCLUSION: Allogeneic BM-MSC, and to a lesser extend ASC, are capable of inducing HLA specific reactivity. These results should be taken into consideration when using allogeneic MSC for clinical therapy

Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets

The age- and cytomegalovirus (CMV)-seropositivity-related changes in subsets and differentiation of circulating T cells were investigated in end-stage renal disease (ESRD) patients (n = 139) and age-matched healthy individuals. The results show that CMV-seropositivity is associated with expansion of both CD4+ and CD8+ memory T cells which is already observed in young healthy individuals. In addition, CMV-seropositive healthy individuals have a more differentiated memory T cell profile. Only CMV-seropositive healthy individuals showed an age-dependent decrease in CD4+ naïve T cells. The age-related decrease in the number of CD8+ naïve T cells was CMV-independent. In contrast, all ESRD patients showed a profound naïve T-cell lymphopenia at every decade. CMV-seropositivity aggravated the contraction of CD4+ naïve T cells and increased the number of differentiated CD4+ and CD8+ memory T cells. In conclusion, CMV-seropositivity markedly alters the homeostasis of circulating T cells in healthy individuals and aggravates the T cell dysregulation observed in ESRD patients

Body mass index and outcome in renal transplant recipients: a systematic review and meta-analysis

BACKGROUND: Whether overweight or obese end stage renal disease (ESRD) patients are suitable for renal transplantation (RT) is often debated. The objective of this review and meta-analysis was to systematically investigate the outcome of low versus high BMI recipients after RT. METHODS: Comprehensive searches were conducted in MEDLINE OvidSP, Web of Science, Google Scholar, Embase, and CENTRAL (the Cochrane Library 2014, issue 8). We reviewed four major guidelines that are available regarding (potential) RT recipients. The methodology was in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and written based on the PRISMA statement. The quality assessment of studies was performed by using the GRADE tool. A meta-analysis was performed using Review Manager 5.3. Random-effects models were used. RESULTS: After identifying 5,526 studies addressing this topic, 56 studies were included. We extracted data for 37 outcome measures (including data of more than 209,000 RT recipients), of which 26 could be meta-analysed. The following outcome measures demonstrated significant differences in favour of low BMI (<30) recipients: mortality (RR = 1.52), delayed graft function (RR = 1.52), acute rejection (RR = 1.17), 1-, 2-, and 3-year graft survival (RR = 0.97, 0.95, and 0.97), 1-, 2-, and 3-year patient survival (RR = 0.99, 0.99, and 0.99), wound infection and dehiscence (RR = 3.13 and 4.85), NODAT (RR = 2.24), length of hospital stay (2.31 days), operation duration (0.77 hours), hypertension (RR = 1.35), and incisional hernia (RR = 2.72). However, patient survival expressed in hazard ratios was in significant favour of high BMI recipients. Differences in other outcome parameters were not significant. CONCLUSIONS: Several of the pooled outcome measurements show significant benefits for ‘low’ BMI (<30) recipients. Therefore, we postulate that ESRD patients with a BMI >30 preferably should lose weight prior to RT. If this cannot be achieved with common measures, in morbidly obese RT candidates, bariatric surgery could be considered. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-015-0340-5) contains supplementary material, which is available to authorized users

Erratum: Body mass index and outcome in renal transplant recipients: a systematic review and meta-analysis

This is an Erratum to BMC Medicine 2015, 13:111 indicating the correct name for one of the authors. Please see related article: http://www.biomedcentral.com/1741-7015/13/11

IL-2 producing memory CD4+ T lymphocytes are closely associated with the generation of IgG-secreting plasma cells

The role of specific CD4(+) T cell subsets in the induction of Immoral immune responses in humans is largely unknown. In this study, the generation of hepatitis B surface Ag-specific CD4(+) T lymphocytes following vaccination was closely monitored and characterized at the single-cell level. The appearance and absolute numbers of hepatitis B surface Ag-specific IL-2 producing effector memory CD4(+) T lymphocytes was solely and tightly related to Ab titers reached. This relation remained present many years after vaccination. Subsequently, a relation was found between Ab titers and number of IL-2 producing memory CD4(+) T lymphocytes for various other Ags. These observations matched the findings of an in vitro assay, using different T cell subsets to induce B cell differentiation into IgG-producing plasma cells. By depleting for IL-2 producing memory T cells, we demonstrated that these cells are important for B cell differentiation into IgG-producing plasma cells. Finally, blocking the action of IL-2 with an IL-2R-alpha Ab inhibited the differentiation of B lymphocytes into IgG-producing plasma cells. Based on these findings, we conclude that the development of Ag-specific IL-2-producing memory T cells appears to be essential for the development of IgG-secreting plasma cells in humans

The Burden of Gastrointestinal Complaints in Kidney Transplant Recipients Using Tacrolimus With and Without Mycophenolate Mofetil: A Randomized Controlled Study.

Background: Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is the immunosuppressive regimen in the majority of solid organ transplant recipients. Gastrointestinal complaints are frequent, which is considered predominantly a side effect of MMF. However, systematic research in this field is lacking. The aim of this study is to systematically investigate the burden of gastrointestinal complaints in TAC-treated kidney transplant recipients with and without MMF. Methods: In a single-center, open-label, randomized controlled trial, low immunological risk recipients were randomized to either TAC and MMF or to TAC monotherapy from 6 months after kidney transplantation onwards [NTR4672],. They filled in the Gastrointestinal Symptom Rating Scale questionnaire, which covers five dimensions (abdominal pain, reflux, indigestion, constipation, and diarrhea), 6, 12, and 15 months after transplantation. Results: Seventy-nine recipients were randomized and 72 completed all questionnaires (34 TACmono and 38 TAC/MMF). At baseline, the mean age was 59 years with 72% male, mean BMI 28 kg/m2, eGFR 55 ml/min/1.73m2, mean daily dose MMF 1200 mg and TAC 5.8 mg, with trough levels of 2.1 mg/L and 7.4 ug/L. Six months after transplantation, 75% of recipients reported troublesome symptoms (score ≥3). Diarrhea was the most troublesome (mean 3.3) and discontinuing MMF significantly reduced it (mean Δ score between month 6 and 15 TAC/MMF -0.9 vs. TACmono -1.8, p=0.03). In recipients with troublesome symptoms, abdominal pain (2.7 to 1.8, p=0.003), indigestion (2.8 to 2.3, p=0.012), and reflux (2.9 to 1.7, p=0.007) significantly decreased over time, independent of MMF use. Conclusion: The majority of kidney transplant recipients with TAC and MMF experienced troublesome gastrointestinal symptoms 6 months after transplantation. While constipation remained troublesome, indigestion, abdominal pain, and reflux improved over time by month 15. Diarrhea only improved after discontinuing MMF

The Burden of Gastrointestinal Complaints in Kidney Transplant Recipients Using Tacrolimus With and Without Mycophenolate Mofetil: A Randomized Controlled Study

Background: Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) is the immunosuppressive regimen in the majority of solid organ transplant recipients. Gastrointestinal complaints are frequent, which is considered predominantly a side effect of MMF. However, systematic research in this field is lacking. The aim of this study is to systematically investigate the burden of gastrointestinal complaints in TAC-treated kidney transplant recipients with and without MMF. Methods: In a single-center, open-label, randomized controlled trial, low immunological risk recipients were randomized to either TAC and MMF or to TAC monotherapy from 6 months after kidney transplantation onwards [NTR4672],. They filled in the Gastrointestinal Symptom Rating Scale questionnaire, which covers five dimensions (abdominal pain, reflux, indigestion, constipation, and diarrhea), 6, 12, and 15 months after transplantation. Results: Seventy-nine recipients were randomized and 72 completed all questionnaires (34 TACmono and 38 TAC/MMF). At baseline, the mean age was 59 years with 72% male, mean BMI 28 kg/m2, eGFR 55 ml/min/1.73m2, mean daily dose MMF 1200 mg and TAC 5.8 mg, with trough levels of 2.1 mg/L and 7.4 ug/L. Six months after transplantation, 75% of recipients reported troublesome symptoms (score ≥3). Diarrhea was the most troublesome (mean 3.3) and discontinuing MMF significantly reduced it (mean Δ score between month 6 and 15 TAC/MMF -0.9 vs. TACmono -1.8, p=0.03). In recipients with troublesome symptoms, abdominal pain (2.7 to 1.8, p=0.003), indigestion (2.8 to 2.3, p=0.012), and reflux (2.9 to 1.7, p=0.007) significantly decreased over time, independent of MMF use. Conclusion: The majority of kidney transplant recipients with TAC and MMF experienced troublesome gastrointestinal symptoms 6 months after transplantation. While constipation remained troublesome, indigestion, abdominal pain, and reflux improved over time by month 15. Diarrhea only improved after discontinuing MMF