Besouw, N.M. van

Systemic varicella zoster virus reactive effector memory T-cells impaired in the elderly and in kidney transplant recipients (Article)

2012-12-01T00:00:00Z

Varicella zoster virus (VZV) infections cause varicella and subsequently herpes zoster upon reactivation. Immune-compromised individuals and the elderly are at high risk of developing herpes zoster due to waning of VZV-specific T-cell immunity. In the present study, a novel functional T-cell assay was developed to test the correlation between age and VZV-specific T-cell responses in peripheral blood from healthy individuals. Secondly, VZV-specific T-cell responses from renal transplant recipients were compared with healthy individuals. Monocytes were differentiated into mature monocyte-derived dendritic cells (moDCs) and were infected with VZV. T-cells were co-cultured with autologous moDCs infected with VZV and subjected to flowcytometric analysis to identify the phenotype (i.e., naïve [NA: CCR7+CD45RO-], central [CM: CCR7+CD45RO+] and effector memory [EM: CCR7-CD45RO+] T-cells) and the frequency of VZV-reactive T-cell subsets by intra-cellular IFN-γ flowcytometry. In contrast to NA and CM T-cells, the frequency of VZV-reactive CD4 and CD8 EM T-cells was inversely correlated with age (P=0.0007 and P=0.01). No difference was found in the percentage of VZV-reactive CD4 NA, CM and EM T-cells between transplant recipients and controls. However, the percentage of VZV-reactive CD8 EM T-cells was significantly lower in transplant recipients compared to controls (P=0.02). In conclusion, moDCs infected with VZV are efficient antigen presenting cells applicable to enumerate and characterize the phenotype and differentiation status of the systemic VZV-specific T-cell response ex-vivo. The data suggest that VZV-reactive EM T-cells are impaired in the elderly and renal transplant recipients.

Vaccine-induced allo-hla-reactive memory T cells in a kidney transplantation candidate (Article)

2011-03-27T00:00:00Z

Background. Allo-human leukocyte antigen (HLA) reactivity by naturally acquired viral-specific memory T cells is common. However, the effect of successful vaccination on the alloreactive memory T-cell repertoire is unclear. We hypothesized that vaccination could specifically induce allo-HLA-reactive memory T cells. Methods. A varicella-zoster virus (VZV) immediate early 62 (IE62)-specific CD8 memory T-cell clone was single cell sorted from a VZV seronegative renal transplant candidate after response to live attenuated varicella vaccination. To analyze the allo-HLA reactivity, the VZV IE62-specific T-cell clone was tested against HLA-typed target cells and target cells transfected with HLA molecules, in both cytokine production and cytotoxicity assays. Results. The varicella vaccine-induced VZV IE62-specific T-cell clone specifically produced interferon-γ when stimulated with HLA-B*55:01-expressing Epstein-Barr virus-transformed B cells and HLA-B*55:01-transfected K562 cells (single HLA antigen expressing cell line [SALs]) only. The clone also demonstrated specific cytolytic effector function against HLA-B*55:01 SALs and phytohemagglutinin blasts. Cytotoxicity assays using proximal tubular epithelial cell and human umbilical vein endothelial cell targets confirmed the kidney tissue specificity of the allo-HLA-B*55:01 reactivity, and the relevance of the cross-reactivity to clinical kidney transplantation. The results also suggest that molecular mimicry, and not bystander proliferation, is the mechanism underlying vaccine-induced alloreactivity. Conclusions. Varicella vaccination generated a de novo alloreactive kidney cell-specific cytolytic effector memory T cell in a patient awaiting renal transplantation. Vaccination-induced alloreactivity may have important clinical implications, especially for vaccine timing and recipient monitoring.

Preeclampsia is associated with increased cytotoxic T-cell capacity to paternal antigens (Article)

2010-11-01T00:00:00Z

Objective: During an uncomplicated pregnancy the conceptus is a semiallogeneic entity in which rejection is prevented by suppression of the maternal immune system. We hypothesized that this suppression is disturbed in patients with preeclampsia and that a maternal immune response to fetal (foreign/paternal) antigens in the fetal-maternal interface may be responsible for local inflammation, with subsequent endothelial dysfunction and systemic disease. Study design: Blood samples were obtained from 14 women with preeclampsia (cases), 14 gestational-age and parity-matched women with uncomplicated pregnancies (controls), and their partners. We determined the partner-specific cytotoxic T-lymphocyte precursor frequency (CTLpf) and the CTLpf directed to unrelated partners with uncomplicated pregnancies. We measured the CTLpf in peripheral blood mononuclear cells (PBMCs) from cases and controls using limited-dilution assays. In addition, proliferation was tested in a mixed-lymphocyte culture (MLR). Results: The partner-specific CTLpf was significantly higher in cases compared with controls (median, 183 [15-338] vs 67 [9-232] per million PBMCs, P = .02). In contrast, in women with uncomplicated pregnancies, the partner-specific CTLpf was down-regulated compared with the CTLpf directed to an unrelated partner who fathered uncomplicated pregnancies (P = .02). No difference was found in partner-specific MLR response between cases and controls. Conclusion: These results suggest that women with preeclampsia have a higher cytotoxic T-cell response to paternal antigens compared with pregnant controls. This insufficiently suppressed immune response may eventually lead to the development of preeclampsia.

Migration of allosensitizing donor myeloid dendritic cells into recipients after liver transplantation (Article)

2010-01-01T00:00:00Z

It is thought, but there is no evidence, that myeloid dendritic cells (MDCs) of donor origin migrate into the recipient after clinical organ transplantation and sensitize the recipient's immune system by the direct presentation of donor allo-antigens. Here we show prominent MDC chimerism in the recipient's circulation early after clinical liver transplantation (LTx) but not after renal transplantation (RTx). MDCs that detach from human liver grafts produce large amounts of pro-inflammatory [tumor necrosis factor alpha and interleukin 6 (IL-6)] and anti-inflammatory (IL-10) cytokines upon activation with various stimuli, express higher levels of toll-like receptor 4 than blood or splenic MDCs, and are sensitive to stimulation with a physiological concentration of lipopolysaccharide (LPS). Upon stimulation with LPS, MDCs detaching from liver grafts prime allogeneic T cell proliferation and production of interferon gamma but not of IL-10. Soluble factors secreted by liver graft MDCs amplify allogeneic T helper 1 responses. In conclusion, after clinical LTx, but not after RTx, prominent numbers of donor-derived MDCs migrate into the recipient's circulation. MDCs detaching from liver grafts produce pro-inflammatory and anti-inflammatory cytokines and are capable of stimulating allogeneic T helper 1 responses, and this suggests that MDC chimerism after clinical LTx may contribute to liver graft rejection rather than acceptance.

The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches (Article)

2009-10-29T00:00:00Z

Estimates of precursor frequency and assessment of functional characteristics of alloreactive CD4+T cells are all biased by the need for long-term culture. In this study, direct visualization of human alloreactive CD4+T cells on the single-cell level was achieved using cell surface expression of CD154 as a tool for identification. The average frequency of alloreactive CD154+CD4+T cells among peripheral blood CD4+T cells was 0.1%, with half of the cells displaying a naive phenotype. The proliferation capacity and expression of cytokines after allogeneic stimulation resided in these CD154+CD4+T cells. The repertoire of alloreactive CD4+T cells was biased to a Th17 response, and on average 24% of alloreactive CD154+CD4+memory T cells produced interleukin-17 (IL-17) after polyclonal stimulation. Unexpectedly, mixed cell cultures from human leukocyte antigen (HLA)-identical donors also generated alloreactive CD154+CD4+T cells and yielded the highest frequency compared with HLA-nonidentical combinations. Therefore, reactivity to minor histocompatibility antigens between HLA-identical subjects appears to be relatively common. Alloreactive HLA-identical T cells did not proliferate or express cytokines, but were driven to proliferation in the presence of exogenous IL-2.

Non-HLA T-cell reactivity during the first year after HLA-identical living-related kidney transplantation (Article)

2009-09-01T00:00:00Z

Background: It has been reported that donor-reactive T-cell responses may decrease during the first year after HLA-mismatched organ transplantation. We wondered whether donor-reactive T-cell responses directed to minor histocompatibility antigens (mHAgs) or other non-HLA antigens also decrease after HLA-identical living-related (LR) kidney transplantation. Methods: We studied donor-reactive T-cell responses by IFN-γ and granzyme B (GrB) Elispot assays in 15 HLA-identical LR kidney transplant recipients before, six months and one yr after transplantation. Third-party reactivity was used as control. Patient and donor peripheral blood mononuclear cells were typed for 11 known mHAgs. Results: During the study period, 60% and 36% of the patients demonstrated donor-reactive IFN-γ and GrB producing cells (pc), respectively. The number of donor-reactive IFN-γ and GrB pc was significantly lower than the number of third-party reactive IFN-γ and GrB pc. After transplantation, donor-reactivity and third-party reactivity were comparable to pre-transplant values. No relation was found in mHAg mismatches between donor and recipient and donor-reactive T-cell response. Conclusions: Donor-reactivity could be detected before and after HLA-identical LR kidney transplantation, but was not related with the number of mHAg mismatches, and did not decrease after transplantation.

A Multiplex Bead Array Analysis to Monitor Donor-Specific Cytokine Responses After Withdrawal of Immunosuppression in HLA-Identical living Related Kidney Transplant Patients (Article)

2009-06-01T00:00:00Z

Immune reactivity after HLA-identical living related (LR) kidney transplantation can be caused by minor histocompatibility antigen and non-HLA antigen mismatches between donor and recipient. In our center, HLA-identical LR kidney transplant recipients receive azathioprine (AZA) or mycophenolate mofetil (MMF) in combination with corticosteroids for 1 year after transplantation. Thereafter, AZA or MMF was withdrawn, and the patients were treated with steroid monotherapy as maintenance therapy. We questioned whether withdrawal of AZA or MMF affected the donor-specific lymphocyte proliferation and cytokine production. Donor and third-party T-cell reactivities were determined by mixed lymphocyte reactions and by cytokine production using multiplex bead array technique. The donor and third-party proliferative capacities were not affected after withdrawal of AZA or MMF. Thirteen of 17 cytokines were detected by the multiplex bead array technique. No differences were observed after third-party induced cytokine production after withdrawal of AZA or MMF. However, production of donor-specific interferon-γ and macrophage inflammatory protein-1β increased after discontinuation of AZA or MMF, but no clinically relevant acute rejection was observed. In conclusion, after HLA-identical LR kidney transplantation, donor-specific cytokine responses can be found when AZA or MMF therapy is discontinued. The clinical relevance of this phenomenon is still not evident.

Deficient TNF-α and IFN-γ production correlates with nondetectable donor-specific cytotoxicity after clinical kidney transplantation (Article)

2009-05-27T00:00:00Z

BACKGROUND.: We previously reported that no cytotoxic T-lymphocyte precursor frequencies (CTLpf) were found in 60% of patients on azathioprine or mycophenolate mofetil+Pred long after kidney transplantation. We questioned whether the absence of donor-specific CTLpf was associated with low levels of stimulatory Th1 (tumor necrosis factor [TNF]-α, interferon [IFN]-α) or high levels of regulatory Th2 (interleukin [IL]-4, IL-6, IL-10) cytokines. METHODS.: In this study, peripheral blood monocyte cells (PBMC) were stimulated with irradiated donor cells. After 7 days, cytokine production was determined by cytokine bead array, and CTLpf by limiting dilution assay. RESULTS.: Patients with detectable CTLpf (ĝ‰¥10/10 PBMC) had significantly higher levels of TNF-α (P=0.04) and IFN-α (P=0.02) than patients with nondetectable CTLpf (<10/10 PBMC). Donor-reactive IL-4, IL-6, and IL-10 production was comparable in both patient groups. Additionally, CTLpf was positively correlated with TNF-α (rs=0.54, P=0.0003) and IFN-α (rs=0.64, P<0.0001) production. CONCLUSION.: The absence of donor-specific CTLp after transplantation correlates with low levels of stimulatory cytokines, not with elevated levels of regulatory cytokines.

T-cell reactivity during tapering of immunosuppression to low-dose monotherapy prednisolone in HLA-identical living-related renal transplant recipients (Article)

2009-03-27T00:00:00Z

BACKGROUND.: In many transplant centers, human leukocyte antigen (HLA)-identical living-related (LR) renal transplant recipients receive standard maintenance immunosuppression from 1 year after transplantation. We questioned whether discontinuation of azathioprine (AZA) or mycophenolate mofetil (MMF) influenced T-cell reactivity, circulating dendritic cell (DC) subsets numbers and their maturation status. METHODS.: Twenty-nine HLA-identical LR renal transplant recipients were withdrawn from AZA or MMF. Thereafter, the patients received only prednisolone. T-cell reactivity was determined by interferon-γ (n=23), interleukin (IL)-10 (n=16), and granzyme B (n=10) Elispot assays. Circulating DC subset numbers and their maturation status determined by CCR2, CCR5, CCR7, and CD83 expression were measured by flow cytometry (n=12). RESULTS.: The number of donor, third-party, and tetanus toxoid-reactive interferon-γ and granzyme-B producing cells was not affected after withdrawal of immunosuppression. Discontinuation of AZA or MMF resulted in significant increased numbers of third-party (P=0.003) and tetanus toxoid-reactive (P=0.008) IL-10 producing cells, and a trend in higher numbers of donor-reactive IL-10 producing cells (P=0.06). No effect was found on the number of circulating DC subsets, but DC was shifted toward a more mature phenotype. CONCLUSIONS.: In HLA-identical LR renal transplant recipients, therapy with AZA and MMF suppress the IL-10 production and the maturation of DC. This suggests that these immunosuppressants may hinder suppression of immune responses in general, including allogeneic responses.

Successful tapering of immunosuppression to low-dose monotherapy steroids after living-related human leukocyte antigen-identical renal transplantation (Article)

2009-03-15T00:00:00Z

Background. Living-related (LR) human leukocyte antigen (HLA)-identical renal transplant (RTx) recipients often receive standard immunosuppression, despite the absence of mismatched major HLA-antigens and the known complications of long-term use of immunosuppression. No data are available on the need for immunosuppression for these specific patients. We wondered whether their immunosuppressive load could be radically reduced. Method. Between November 1982 and November 2005, 83 LR HLA-identical RTx were performed in our center. Their unadjusted graft survival was 74% at 10 years. In 29 patients (median time after transplantation 5.6 [range 1.0-21.4] years) with stable uncompromised renal function, we tapered their immunosuppression from triple or dual therapy to prednisolone 5 mg/day. Follow up on prednisolone monotherapy was at least 24 months. Results. In 27 of 29 patients reduction of immunosuppression to prednisolone monotherapy was uneventful. One patient, using dual therapy, developed JC-virus nephropathy resulting in graft loss. One refused further discontinuation of his medication. Four (15%) of the 27 patients on monotherapy developed biopsy-proven recurrence of their original disease. Only one of them showed a transient decline in renal function. One additional patient developed minor proteinuria and a rise in serum creatinine level, as a result of chronic urinary tract infections. The remaining 23 of 27 patients (85%) had an uneventful follow up during 24 months prednisolone monotherapy. Conclusion. We conclude that HLA-identical LR RTx recipients who are at least 1 year after transplantation might be treated with low-dose steroid monotherapy. Close surveillance of patients for recurrence of their original disease is recommended to allow for potential early therapeutic intervention.

Tapering immunosuppressive therapy significantly improves in vivo cutaneous delayed type hypersensitivity responses (Article)

2008-07-01T00:00:00Z

Immunosuppressive therapy affects cell-mediated immunity and thereby increases the frequency of infections and malignancies in transplanted patients. We questioned whether reducing the immunosuppressive dose in stable kidney transplant patients has an in vivo effect on cutaneous delayed type hypersensitivity responses (DTH) reflecting cell-mediated immunity. We measured DTH responses to recall antigens (Tetanus, Diphteria, Streptococcus, Tuberculin, Candida, Trychophyton, Proteus, glycerin control) on the volar surface of the forearm in patients before and after successful reduction (50%) of the dose of mycophenolate mofetil (MMF) or azathioprine (AZA). In addition, we tested healthy individuals who were age- and sex-matched to the patient group. Results of the skin reaction test were calculated as the sum in millimeters (mm) of all positive reactions (score), and as the number of positive antigens. Patients treated with a high dose of MMF or AZA had a significantly lower test score compared to healthy controls (p = 0.01). Also the number of positive antigens was reduced in patients compared to healthy controls (p = 0.02). After reduction of the MMF or AZA dose, the test score and the number of positive antigens increased significantly (p = 0.02, p = 0.01, respectively) to comparable scores of healthy controls. Additionally, the mycophenolic acid (MPA) trough level was negatively correlated with the test score (p = 0.006) and number of positive antigens (p = 0.004). In conclusion, successful tapering of the MMF or AZA dose in kidney transplant patients more than 2 years after transplantation favorably affects the in vivo DTH response, reflecting an improvement of the general immunity, facilitating the defense against infection and malignancies.

After discontinuation of calcineurin inhibitors, tapering of mycophenolate mofetil further impairs donor-directed cytotoxicity (Article)

2008-03-01T00:00:00Z

Background: Recently, we described a significant decrease in donor-specific cytotoxic T-lymphocyte precursor frequency (CTLpf) after discontinuation of calcineurin inhibitors (CNI), while the proliferative capacity in mixed lymphocyte culture (MLC), and the number of interferon-γ (IFN-γ) producing cells (pc) in Elispot remained unchanged. Methods: We tested T-cell reactivity in CNI free patients with stable renal graft function, on mycophenolate mofetil (MMF) or azathioprine (AZA) plus prednisone, who were tapered to 50% of their MMF or AZA dose. Results: Furthermore, tapering of the MMF or AZA dose resulted in a decrease of donor-reactive CTLpf in all patients with detectable CTLpf. Detectable numbers decreased from a median of 32 to 8 CTLp/106 peripheral blood mononuclear cell (PBMC). No effect on third-party reactive CTLpf was found, while the T-cell reactivity to donor and third-party cells as tested in MLC and in IFN-γ Elispot was not affected either by tapering of immunosuppression. Third-party reactivity was significantly higher than donor-specific reactivity in all tests. A control group showed no changes in any of the in vitro assays. Conclusion: Both withdrawal of CNI and tapering of MMF or AZA dose decreases the donor-specific CTLpf. Our data suggest that reduction of immunosuppression results in a specific decrease of donor-directed cytotoxic capacity of immunocompetent cells, while their proliferation and cytokine production capacity remained unchanged. Immunosuppression hinders development of cytotoxic non-responsiveness.

Peripheral blood manipulation significantly affects the result of dendritic cell monitoring (Article)

2007-04-01T00:00:00Z

It has been postulated that the plasmacytoid/myeloid dendritic cell ratio (pDC/mDC) reflects immune reactivity, and can therefore be used to monitor transplant recipients. We investigated the influence of Ficoll-Paque separation and PBMC cryopreservation on the pDC/mDC ratio and the expression of maturation markers, e.g. chemokine receptors (CKRs) CCR7, CXCR4, and CCR5, in comparison to fresh blood cells. Fractions of pDCs and mDCs, and CKR expression were measured by flow cytometry in fresh blood, in Ficoll-isolated PBMCs and in cryopreserved PBMCs from healthy individuals and kidney transplant recipients. Ficoll-isolation of PBMCs resulted in higher pDC/mDC ratios in both groups compared to fresh blood cells resulting from a relatively large increase in pDCs compared to mDCs. The pDC/mDC ratio increased further after cryopreservation of PBMCs from kidney transplant recipients. Ficoll-isolation and cryopreservation of PBMCs affected the proportion of mDCs and pDCs positive for CKRs, and their expression levels resulting in a more mature phenotype. In conclusion, the pDC/mDC ratio and pDC or mDC maturation status based on CKR expression, is dependent on manipulation of PBMCs. Therefore, fresh blood is preferable for monitoring purposes in transplant patients, as only these cells reflect the in vivo immune-status of patients accurately.

Stable T-cell reactivity after successful tapering of azathioprine in HLA-identical living-related kidney transplant recipients despite minor histocompatibility antigen mismatches (Article)

2007-02-01T00:00:00Z

Background. Human leukocyte antigen (HLA)-identical living-related (LR) kidney transplant recipients often receive the standard regimen of immunosuppression. We wondered whether these patients should be exposed to the side effects of these drugs any longer. Safe tapering of immunosuppression should not result in rejection and high donor-directed T-cell responses. In the present study, we investigated the effect of tapering azathioprine (AZA) on T-cell reactivity. Methods. Fifteen HLA-identical LR kidney transplant recipients receiving a median of 150 mg/day AZA and 5-10 mg/day prednisone were tapered to a median of 50 mg/day AZA. Donor-, third-party and tetanus toxoid (TET)-reactivity were determined in interferon (IFN)-γ and interleukin (IL)-13 Elispot assays, which reflect the T-helper (Th)1 and T-helper (Th)2 response. Results. After the tapering of AZA, none of the patients developed acute rejection and the renal function remained stable, even at 1-year follow-up. The frequency of donor-specific IFN-γ and IL-13 producing cells (pc) was low. Tapering of AZA did not influence the frequency of both IFN-γ and IL-13 pc. Also, the reactivity against third-party cells and TET remained unchanged. Conclusions. The AZA-dose can be safely reduced in recipients of an HLA-identical LR kidney transplant without affecting kidney function and without increasing T-cell responses directed against donor or other antigens.

Tapering immunosuppression in recipients of living donor kidney transplants. (Article)

2004-07-01T00:00:00Z

We have previously suggested that the in vitro donor-specific cytotoxic T-lymphocyte precursor (CTLp) assay can guide us to identify patients in which the immunosuppressive load can be tapered. In a clinical trial we had observed that a low (<10/10(6) PBMC) frequency of these CTLp was predictive for an uneventful rejection-free clinical course in patients that were converted from calcineurin inhibitors to mycophenolate mofetil or azathiopine. In the present prospective study in 81 stable kidney transplant recipients, already converted from calcineurin inhibitors, we measured CTLp frequencies and reduced the immunosuppressive load on a routine basis when CTLp were <10/10(6) PBMC. Donor-specific cytotoxicity could not be measured in 50/81 patients, while their reactivity against third-party lymphocytes was not impaired. These 50 patients were tapered in their immunosuppression. Only in one patient, who had stopped all his medication, was a rejection episode diagnosed. We conclude that in patients with a low donor-specific CTLp frequency it is safe to reduce the immunosuppression.

Rejection Pathways in Heart Transplant Recipients (Doctoral Thesis)

1999-02-17T00:00:00Z

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.

Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study (Article)

1999-01-01T00:00:00Z

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.

Effect of mycophenolate mofetil on erythropoiesis in stable renal transplant patients is correlated with mycophenolic acid trough levels (Article)

1999-01-01T00:00:00Z

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.