Jeroen H. Gerrits

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

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 recipients immune system by the direct presentation of donor allo‐antigens. Here we show prominent MDC chimerism in the recipients 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 recipients 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. Liver Transpl 16:12–22, 2010.

Successful Tapering of Immunosuppression to Low-Dose Monotherapy Steroids After Living-Related Human Leukocyte Antigen-Identical Renal Transplantation

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.

T-Cell Reactivity During Tapering of Immunosuppression to Low-Dose Monotherapy Prednisolone in HLA-Identical Living-Related Renal Transplant Recipients

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-&ggr; (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-&ggr; 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.

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

Abstract:u2002 Background:u2002 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.

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

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-gamma and macrophage inflammatory protein-1beta 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.