Pathways of helper CD4 T cell allorecognition in generating alloantibody and CD8 T cell alloimmunity.

BACKGROUND: The relative contributions of the "direct" and "indirect" pathways of CD4 T cell allorecognition in providing help for generating effective humoral and CD8 T cell alloimmunity remain unclear. Here, the generation of alloantibody and cytotoxic CD8 T cell responses to a vascularized allograft were examined in a murine adoptive-transfer model in which help could only be provided by transferred CD4 T cells recognizing alloantigen exclusively through the direct pathway. METHODS: Rejection kinetics and the development of alloantibody and cytotoxic CD8 T cell responses to MHC-mismatched H-2d heart grafts were compared when CD4 T cell help was present (wild-type H-2d recipients), or absent (CD4 T cell deficient, MHC class II-/- H-2b recipients [B6CII-/-]), or available only through the direct pathway (B6CII-/- mice reconstituted with wild-type CD4 T cells). RESULTS: BALB/c allografts were rejected by B6 mice rapidly (median survival time [MST] 7 days) with strong CD8 T cell effector and alloantibody responses, but were rejected by B6CII-/- mice more slowly (MST 23 days), with markedly reduced CD8 T cell responses and no detectable alloantibody. CD4 T cell reconstitution of B6CII-/- recipients accelerated heart graft rejection to near that of wild-type recipients (MST 13 days), with complete restoration of cytotoxic CD8 T cell responses but without detectable IgM or IgG alloantibody. CONCLUSIONS: Different pathways of helper T cell allorecognition are responsible for generating humoral and CD8 T cell alloimmunity. CD4 T cell help provided exclusively through the direct pathway generates strong cytotoxic CD8 T cell responses that effect rapid heart graft rejection.

Anthracycline-based chemotherapy as first-line treatment in adults with malignant posttransplant lymphoproliferative disorder after solid organ transplantation.

BACKGROUND: Recommended first-line treatment for posttransplant lymphoproliferative disorder (PTLD) is reduction in immunosuppressive therapy, irrespective of histopathological type. Second-line treatment with chemotherapy is generally reserved for tumors that fail to respond to reduced immunosuppression. In view of the similarities between monomorphic PTLD and non-Hodgkin's lymphoma in the general population, our policy is to treat monomorphic PTLD with anthracycline-based chemotherapy as first-line treatment. METHODS: A retrospective single-center analysis of 18 adults who developed PTLD following liver or kidney transplantation was undertaken, with particular emphasis on tumor histology, treatment received, and clinical outcome. RESULTS: Of the 18 patients with PTLD, 13 had high-grade malignant lymphoma on diagnostic biopsy and received anthracycline-based chemotherapy and reduction in immunosuppression as first-line therapy. Nine (69%) of the 13 patients achieved complete remission and eight (62%) remained in complete remission five years after diagnosis. There was no graft loss from rejection or drug toxicity. Four (22%) patients had polymorphic PTLD on diagnostic biopsy (of which two were re-classified as monomorphic) and one had a low-grade malignant lymphoma. All five patients were treated by reduction in immunosuppression without chemotherapy and were in complete remission at a median of two years after diagnosis. Overall, complete remission was seen in 14 out of 18 patients (78%) at one year following diagnosis. CONCLUSION: The use of anthracycline-based chemotherapy and reduction of immunosuppression as first-line treatment in adults with monomorphic PTLD is well tolerated and achieves sustained complete remission in around 70% of patients with a low risk of graft loss.

What we CAN do about chronic allograft nephropathy: role of immunosuppressive modulations.

Given the potency of modern immunosuppressive agents, kidney transplantation across alloantingen barriers is a routine phenomenon with excellent 1-year graft survival in most centers. However, the improvement in 1-year graft survival has not been matched by improvements in long-term graft function and chronic allograft nephropathy (CAN) remains the second commonest cause of graft attrition over time. Calcineurin inhibitors, namely cyclosporine A (CyA) and tacrolimus, have been implicated as causal agents in the development of the fibrotic processes that are the hallmarks of CAN. Many studies have, therefore, concentrated on the improvement of long term graft function through the modulation of immunosuppressive therapy. It is the purpose of this review to describe and appraise the available evidence for the prevention and management of CAN through modulation of immunosuppressive agents.

Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy.

Effective immunosuppression is an essential pre-requisite for successful organ transplantation and improvements in outcome after transplantation have to a large extent been dependent on developments in immunosuppressive therapy. Here we provide an overview of the different immunosuppressive agents currently used in solid organ transplantation. A historical perspective on the development of immunosuppression for organ transplantation is followed by a review of the individual agents, with a focus on their mechanism of action and efficacy. Steroids, anti-proliferative agents (azathioprine and mycophenolate), calcineurin inhibitors (cyclosporine and tacrolimus) and TOR inhibitors (sirolimus and everolimus) are discussed along with both polyclonal and monoclonal antibody preparations. Many of the key clinical trials that underpin current clinical usage of these agents are described and side-effects of the different agents are highlighted. Finally, a number of newer agents still in various stages of clinical development are briefly considered.

Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation.

Post-transplant lymphoproliferative disorders (PTLD) are a well-recognised and potentially fatal complication after solid organ transplantation. They include a spectrum of disorders ranging from benign hyperplasia to invasive malignant lymphoma. The majority of cases are associated with Epstein Barr virus (EBV)-driven tumour formation in B cells and are a consequence of the detrimental effect of immunosuppressive agents on the immune-control of EBV. This review provides an update on the pathogenesis and clinical features of PTLD after solid organ transplantation and discusses recent progress in management. Reduction in immunosuppressive therapy remains a key component of therapy for EBV-positive PTLD and may lead to remission in early disease. Chemotherapy is used when reduced immunosuppression fails to control early disease and as initial therapy for many cases of late disease. Unfortunately, the mortality for PTLD that fails to respond to a reduction in immunosuppression remains high. Newer treatments include manipulation of the cytokine environment, B lymphocyte depleting antibodies and adoptive T cell immunotherapy using allogeneic or autologous EBV-specific cytotoxic T lymphocytes. Although early results appear promising, well-designed clinical trials are needed to assess the efficacy of these novel approaches. EBV vaccination may in the future prove an effective prophylaxis against EBV-driven PTLD but until then, avoiding excessive immunosuppressive therapy may help minimise the risk of PTLD.

Recipients who receive a human leukocyte antigen-B compatible cadaveric liver allograft are at high risk of developing acute graft-versus-host disease.

Acute graft-versus-host disease (GvHD) is an uncommon but often fatal complication after orthotopic liver transplantation (OLT). To determine whether there is an association between human leukocyte antigen (HLA) matching and the development of GvHD after cadaveric OLT, we undertook a retrospective, single-center analysis of 412 consecutive adult recipients where HLA typing data was available. Seven (1.7%) recipients developed acute GvHD, and six died from their disease. Donor compatibility at HLA-B but not at HLA-A or -DR was identified as a significant risk factor for the development of GvHD. Of 14 recipients with no HLA-B mismatches, 3 (21%) developed GvHD (odds ratio 27, P<0.001). Conversely, of 262 recipients mismatched at both HLA-B loci, only 1 (0.4%) developed GvHD (odds ratio 0.09, P<0.01). Our findings suggest that patients receiving a liver allograft with no HLA-B mismatched antigens are at increased risk of developing GvHD.

Acute graft versus host disease following liver transplantation: the enemy within.

This article reviews acute graft vs. host disease (GVHD) as a complication of orthotopic liver transplantation (OLT). The incidence, presentation, clinical course and outcome of GVHD after OLT are summarized and the pathogenesis is discussed, drawing parallels with GVHD after allogeneic haematopoietic stem cell transplantation. Risk factors for GVHD after OLT are examined and the potential role of donor lymphocyte macrochimerism in the recipient peripheral blood as a diagnostic aid for GVHD is discussed. Finally, treatment of GVHD after OLT is reviewed with particular emphasis on the potential role of some of the newer biological agents.

Monitoring systemic donor lymphocyte macrochimerism to aid the diagnosis of graft-versus-host disease after liver transplantation.

BACKGROUND: The diagnosis of graft-versus-host disease (GvHD) after liver transplantation can be difficult because early symptoms are often nonspecific. In this study, the presence of donor lymphocyte macrochimerism in recipient peripheral blood was examined as a diagnostic aid for GvHD after cadaveric donor liver transplantation. METHODS: Between 1996 and 2002, 33 liver transplant recipients with a clinical suspicion of GvHD (skin rash, diarrhea, pyrexia, pancytopenia, or anemia, without an obvious alternative cause) were investigated for peripheral blood donor lymphocyte macrochimerism. Donor macrochimerism was determined at the time of first clinical presentation by a low-sensitivity polymerase chain reaction (PCR) to detect donor human leukocyte antigen (HLA) alleles using genomic DNA extracted from recipient peripheral blood. Where donor HLA alleles were detected, the percentage of donor T cells was quantified by two-color flow cytometric analysis using antibodies specific for mismatched donor and recipient HLA alleles. The relationship between the presence or absence of donor lymphocyte macrochimerism and final diagnoses based on clinical and histological criteria was examined. RESULTS: Seven of the 33 patients were PCR positive for donor HLA alleles. All had macrochimerism, with donor T lymphocyte levels ranging from 4% to 50% of circulating lymphocytes. All seven patients had normal liver function tests, skin rash, and diagnosis of GvHD histologically confirmed by skin or gut biopsies. Twenty-six patients were PCR negative, and, in 23, an alternative diagnosis was eventually established. The remaining three patients made a rapid and spontaneous recovery with no further symptoms suggestive of GvHD. CONCLUSIONS: Donor lymphocyte macrochimerism was present in all patients in whom the diagnosis of GvHD was confirmed. In patients with symptoms consistent with GvHD and a negative PCR for donor HLA, an alternative diagnosis was eventually established or the patients recovered spontaneously. Detection of donor HLA alleles in recipient peripheral blood by PCR is a useful diagnostic tool for GvHD after liver transplantation.