13 research outputs found
Rejection Pathways in Heart Transplant Recipients
Since the beginning of this century experimental heart transplantations in animal
studies were performed.' These studies were started in Rotterdam in the seventies
to compare heterotopic and orthotopic heart transplantations, and to study the
process of chronic rejection.
The history of the first human heart transplantation started in South-Africa and it was
carried out by Barnard in 1967. Several cardiac surgeons around the world initiated
new transplantation programmes. However, the problems with patient and donor
organ selection as well as with immunosuppression, severe rejection and infection
were common. This meant in 1968, only 22% of all transplants survived after the first
year.6 Consequently, many centres stopped their programmes.
Heart transplantation, as a routine treatment for organ failure, only became possible
with the development in 1973 of the endomyocardial biopsy technique for monitoring
acute rejection? and in 1975 by the further discovery of cyclosporin A. In the early
eighties cyclosporin A was successfully introduced as an immunosuppressive
medicine post clinical heart transplantation.' Cyclosporin A acts by binding to
calmodulin and thereby inhibits the transcription of the IL-2 and IFN-y gene." With
the development of these new processes, a 50% survival rate after 5 years was
achieved in 1982
The role of follicular T helper cells in the humoral alloimmune response after clinical organ transplantation
Over the past decade, antibody-mediated or humoral rejection in combination with development of de novo donor-specific antibodies (DSA) has been recognized as a distinct and common cause of transplant dysfunction and is responsible for one-third of the failed allografts. Detailed knowledge of the mechanisms that initiate and maintain B-cell driven antidonor reactivity is required to prevent and better treat this antidonor response in organ transplant patients. Over the past few years, it became evident that this response largely depends on the actions of both T follicular helper (Tfh) cells and the controlling counterparts, the T follicular regulatory (Tfr) cells. In this overview paper, we review the latest insights on the functions of circulating (c)Tfh cells, their subsets Tfh1, Tfh2 and Tfh17 cells, IL-21 and Tfr cells in antibody mediated rejection (ABMR). This may offer new insights in the process to reduce de novo DSA secretion resulting in a decline in the incidence of ABMR. In addition, monitoring these cell populations could be helpful for the development of biomarkers identifying patients at risk for ABMR and provide novel therapeutic drug targets to treat ABMR
Peripheral monitoring of direct and indirect alloantigen presentation pathways in clinical heart transplant recipients
It has been reported that the response to alloantigens presented by the direct and indirect pathway may be of differential relevance after human kidney transplantation. Accordingly, we monitored these routes in peripheral blood mononuclear cells (PBMC) of heart transplant patients from before transplantation and up to 2 years thereafter in an attempt to find a correlation with the clinical status of the patients. Both before and after transplantation, comparable proportions of PBMC samples reacted in mixed lymphocyte culture to nondepleted donor spleen cells (direct route), but never to donor cells depleted for antigen-presenting cells (indirect route). In contrast, the latter route could easily be activated by a nominal antigen and persisted after transplantation, although the proportion of PBMC samples responding was significantly suppressed, irrespective of the occurrence of rejection. Consequently, complete removal of antigen-presenting cells from the stimulator population in a mixed lymphocyte culture with PBMC as responder is not a suitable tool for measuring indirect presentation of alloantigens, and therefore not relevant for monitoring the immunological status of heart transplant recipients
Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients
Background: FoxP3+ follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5–7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched healthy individuals served as controls. Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients (p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between
Donor-specific ELISPOT assay for predicting acute rejection and allograft function after kidney transplantation
Acute rejection remains an important problem after kidney transplantation. Enzyme-linked immunosorbent spot (ELISPOT) assay has been investigated extensively and has shown promising results as a predictor of allograft rejection. The objective of this study was to systematically review and analyze the predictive value of the donor-specific ELISPOT assay to identify recipients at risk for acute rejection. Electronic databases were searched for stud
Donor-reactive cytokine profiles after HLA-identical living-related kidney transplantation
Background. After HLA-identical living-related (LR) kidney transplantation, only non-HLA antigen mismatches between donor and recipient may exist. We questioned whether donor-reactive responses against non-HLA antigens could be found after HLA-identical LR kidney transplantation, and wondered whether donor reactivity in the HLA-identical setting was different from the HLA-mismatched setting during immunological quiescence. Healthy individuals served as controls. Methods. Elispot assays were performed to determine the number of alloreactive IFN-γ-producing cells (pc), IL-10 pc, granzyme B (GrB) pc and IL-13 pc from peripheral blood mononuclear cells (PBMC) of HLA-identical, HLA-mismatched LR kidney transplant recipients and healthy individuals. Results. The frequency of alloreactive IFN-γ pc, IL-13 pc and GrB pc was higher in healthy individuals compared to both transplant patient groups. In the HLA-identical group, significantly higher numbers of donor-reactive IL-10 pc were found compared to their autologous control. These frequencies were also higher compared to the HLA-mismatched and healthy control group. The number of donor-reactive GrB pc was higher in the HLA-mismatched group than in the HLA-identical group. Donor-reactive IFN-γ pc and IL-13 pc were comparable in both transplant groups. Conclusions. In recipients of HLA-identical LR kidney transplant, high donor-reactive IL-10 pc, in combination with low donor-reactive IFN-γ pc, IL-13 pc and GrB pc, suggests active downregulation of reactivity against non-HLA molecules
Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study
BACKGROUND: Combining cyclosporin (CsA) and prednisone with mycophenolate
mofetil (MMF) results in a significant reduction in the rate of
biopsy-proven acute rejection after kidney transplantation. This is
achieved with a standard daily MMF dosage of 2 or 3 g. Whether monitoring
of the pharmacologically active metabolite mycophenolic acid (MPA) will
lead to improved safety and efficacy is unclear. METHODS: We monitored MPA
trough levels in 18 kidney transplant recipients treated with CsA,
prednisone, and MMF (63 samples) and in 11 patients (31 samples) treated
with prednisone and MMF only, in a cross-sectional study. All patients
were at least 3 months after transplantation with stable graft function.
All patients were treated with 2 g MMF for at least 3 months and 10 mg
prednisone. RESULTS: The MPA trough levels in the CsA-treated patients
were significantly lower (P<0.0001; Mann-Whitney) than those in patients
on MMF and prednisone only (mean MPA levels 1.98+/-0.12 vs 4.38+/-0.40
mg/l respectively). CONCLUSIONS: Although all patients were treated with
an identical MMF dose, a significant difference was found in the MPA
trough levels between CsA- vs non-CsA-treated patients. This suggests that
CsA influences the MPA trough level. The level at which CsA affects the
MPA trough levels is unclear
A systematic review and meta-analysis of enzyme-linked immunosorbent spot (ELISPOT) assay for BK polyomavirus immune response monitoring after kidney transplantation
BK virus (BKV) infection after kidney transplantation can cause BKV nephropathy (BKVAN) resulting in graft dysfunction and allograft loss. The treatment for BKVAN is reduction of the immunosuppressive load which increases the risk of kidney transplant rejection. There is no biomarker to monitor BKV activity besides BK viral load. The valu
The direct and indirect allogeneic presentation pathway during acute rejection after human cardiac transplantation
Alloreactive T cells may be activated via a direct or an indirect antigen presentation pathway. We questioned whether the frequency of interferon (IFN)-γ producing cells determined by enzyme-linked immunospot (ELISPOT) assay is an effective tool to monitor the direct and/or indirect presentation pathway. Secondly, we wondered whether early and late acute rejection (AR) are associated with both pathways. Before (n = 15), during (n = 18) and after (n = 16) a period of AR, peripheral blood mononuclear cell (PBMC) samples were tested from 13 heart transplant recipients. The direct presentation pathway was always present. The number of IFN-γ producing cells reactive to this pathway increased significantly (P = 0.04) during AR and the number decreased (P = 0.005) after AR therapy. In contrast, the indirect allogeneic presentation pathway was present in only eight of 18 AR samples. When the indirect presentation pathway was detectable, it increased significantly during AR. Five of eight of these AR occurred more than 6 months after transplantation. The ELISPOT assay, enumerating alloreactive IFN-γ producing cells, is a valuable tool to determine the reactivity via both the direct and the indirect presentation pathway. The direct presentation pathway always plays a role in AR, while the indirect pathway contributes especially to late AR
Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels
BACKGROUND: Both mycophenolate mofetil (MMF) and azathioprine (AZA) are
immunosuppressive drugs that inhibit purine synthesis. In theory, MMF
selectively inhibits lymphocyte proliferation, while AZA has well-known
effects on red blood cells and thrombocytes as well. In renal transplant
recipients we replaced CsA therapy by MMF in an attempt to reduce the
immunosuppressive load 1 year after kidney transplantation. During this
study we observed the effect of MMF on haematological parameters such as
haemoglobin (Hb), leukocytes, and thrombocytes. METHODS: One year after
kidney transplantation 26 stable patients were converted from cyclosporin
A (CsA) to MMF (2 g/day). Thereafter, these patients were tapered twice in
their MMF dose from 2 g to 1.5 g (4 months after conversion) and from 1.5
to 1 g (8 months after conversion) per day. The Hb levels, leukocyte and
thrombocyte counts, and mycophenolic acid (MPA) trough levels were
routinely measured. RESULTS: After conversion from CsA to MMF not only
creatinine levels and the number of leukocytes, but also the haemoglobin
(Hb) level significantly decreased in 21/26 patients (P=0.0004). In eight
patients the Hb level dropped more than 1 mmol/l (=1.61 g/dl). Only in two
of eight patients was an explanation for blood loss found. The effect on
Hb level did not ameliorate after the first MMF dose reduction to 1.5
g/day. After tapering the MMF dose to 1 g/day, the Hb approached the
pre-conversion level. Not only the MMF dose but also the mycophenolic acid
(MPA) trough level correlated with the Hb level. CONCLUSIONS: After
conversion from CsA to MMF 1 year after kidney transplantation, a decrease
in Hb level and leukocyte count was observed. The MPA trough level
correlated also with the Hb level. The effect on the Hb level was
reversible after dose reduction. This finding suggests that MMF exerts a
negative effect on erythropoietic cells