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1.
Xenotransplantation ; 27(1): e12552, 2020 01.
Article in English | MEDLINE | ID: mdl-31544995

ABSTRACT

BACKGROUND: We have recently demonstrated that human-CD47 (hCD47) expressed on endothelial cells of porcine lung xenografts extended median graft survival from 3.5 days to 8.7 days in baboons. Intra-bone bone marrow transplantation (IBBMTx) in a pig-to-baboon model was previously shown to markedly prolong the duration of macrochimerism up to 21 days from 1 to 4 days by intravenous BMTx. We now examined whether the use of hCD47 transgenic (Tg) BM further prolonged the duration of chimerism following IBBMTx. We then tested if lung xenograft survival was prolonged following IBBMTx. METHODS: Baboons received GalTKO-hCD47/hCD55Tg (n = 5) or -hCD55Tg (n = 1) or -hCD46/HLA-E Tg (n = 1) pig IBBMTx. Macrochimerism, anti-pig T cells and antibody responses were assessed. Animals received lung xenografts from either hCD47+ or hCD47- porcine lungs 1-3 months later. RESULTS: All baboons that received hCD47Tg porcine IBBM maintained durable macrochimerism >30 days, and two maintained chimerism for >8 weeks. Notably, anti-pig antibody levels decreased over time and anti-pig cellular unresponsiveness developed following IBBMTx. Lungs from hCD47Tg IBBMTx matched pigs were transplanted at day 33 or day 49 after IBBMTx. These animals showed extended survival up to 13 and 14 days, while animals that received lungs from hCD47 negative pigs displayed no prolonged survival (1-4 days). CONCLUSION: This is the first report demonstrating durable macrochimerism beyond 8 weeks, as well as evidence for B cell tolerance in large animal xenotransplantation. Using hCD47Tg pigs as both IBBMTx and lung donors prolongs lung xenograft survival. However, additional strategies are required to control the acute loss of lung xenografts.


Subject(s)
B-Lymphocytes/immunology , Bone Marrow Transplantation , CD47 Antigen/metabolism , Lung Transplantation , Animals , Animals, Genetically Modified , Bone Marrow/surgery , CD47 Antigen/genetics , Cells, Cultured , Chimerism , Graft Survival , Humans , Immune Tolerance , Papio , Swine , Transplantation, Heterologous
2.
Curr Opin Organ Transplant ; 24(5): 517-521, 2019 10.
Article in English | MEDLINE | ID: mdl-31385887

ABSTRACT

PURPOSE OF REVIEW: Xenotransplantation offers the opportunity to alleviate the imbalance between the demand of patients with end stage organ failure and the supply of organs available for transplantation but remains aspirational. This review highlights how collaboration between academia and industry are essential for success. RECENT FINDINGS: The science of xenotransplantation has accelerated in recent years with key discoveries in genetic engineering, enabling disruption of genes facilitating rejection, and transgenic expression of desired human genes. Combined with similar progress directed toward induction of transplant tolerance, the stage has been set for meaningful progress. These advances are reviewed in detail elsewhere in this volume and argue that the breakthroughs needed to deliver substantial cross-species organ survival have largely been achieved, heralding a liminal stage of human xenotransplantation. However, xenotransplantation as a meaningful therapy for medically refractory end organ failure will not be realized through scientific innovation alone. The advent of broadly available, therapeutic xenogeneic tissues requires extensive development and regulatory expertise; the biotechnology/pharmaceutical industry can provide extensive resources and expertise in those essential areas. SUMMARY: Successful delivery of xenotransplantation as an available therapy for curing end stage organ failure is best accomplished through partnership and collaboration between academia and industry.


Subject(s)
Intersectoral Collaboration , Organ Transplantation , Tissue Donors/supply & distribution , Transplantation, Heterologous , Animals , Animals, Genetically Modified , Graft Rejection , Humans , Tissue and Organ Procurement , Transplantation Tolerance
3.
Xenotransplantation ; 25(5): e12391, 2018 09.
Article in English | MEDLINE | ID: mdl-29527745

ABSTRACT

BACKGROUND: Despite recent progress in survival times of xenografts in non-human primates, there are no reports of survival beyond 5 days of histologically well-aerated porcine lung grafts in baboons. Here, we report our initial results of pig-to-baboon xeno-lung transplantation (XLTx). METHODS: Eleven baboons received genetically modified porcine left lungs from either GalT-KO alone (n = 3), GalT-KO/humanCD47(hCD47)/hCD55 (n = 3), GalT-KO/hD47/hCD46 (n = 4), or GalT-KO/hCD39/hCD46/hCD55/TBM/EPCR (n = 1) swine. The first 2 XLTx procedures were performed under a non-survival protocol that allowed a 72-hour follow-up of the recipients with general anesthesia, while the remaining 9 underwent a survival protocol with the intention of weaning from ventilation. RESULTS: Lung graft survivals in the 2 non-survival animals were 48 and >72 hours, while survivals in the other 9 were 25 and 28 hours, at 5, 5, 6, 7, >7, 9, and 10 days. One baboon with graft survival >7 days, whose entire lung graft remained well aerated, was euthanized on POD 7 due to malfunction of femoral catheters. hCD47 expression of donor lungs was detected in both alveoli and vessels only in the 3 grafts surviving >7, 9, and 10 days. All other grafts lacked hCD47 expression in endothelial cells and were completely rejected with diffuse hemorrhagic changes and antibody/complement deposition detected in association with early graft loss. CONCLUSIONS: To our knowledge, this is the first evidence of histologically viable porcine lung grafts beyond 7 days in baboons. Our results indicate that GalT-KO pig lungs are highly susceptible to acute humoral rejection and that this may be mitigated by transgenic expression of hCD47.


Subject(s)
Animals, Genetically Modified/immunology , CD47 Antigen/immunology , Graft Rejection/immunology , Graft Survival/immunology , Papio/immunology , Animals , Graft Rejection/pathology , Heterografts/immunology , Humans , Lung/immunology , Lung Transplantation/methods , Swine , Transplantation, Heterologous/methods , Transplants/immunology
4.
Circulation ; 124(2): 196-205, 2011 Jul 12.
Article in English | MEDLINE | ID: mdl-21690493

ABSTRACT

BACKGROUND: Ligands activating the transcription factor peroxisome proliferator-activated receptor-γ (PPARγ) have antiinflammatory effects. Vascular rejection induced by allogeneic T cells can be responsible for acute and chronic graft loss. Studies in rodents suggest that PPARγ agonists may inhibit graft vascular rejection, but human T-cell responses to allogeneic vascular cells differ from those in rodents, and the effects of PPARγ in human transplantation are unknown. METHODS AND RESULTS: We tested the effects of PPARγ agonists on human vascular graft rejection using a model in which human artery is interposed into the abdominal aorta of immunodeficient mice, followed by adoptive transfer of allogeneic (to the artery donor) human peripheral blood mononuclear cells. Interferon-γ-dependent rejection ensues within 4 weeks, characterized by intimal thickening, T-cell infiltrates, and vascular cell activation, a response resembling clinical intimal arteritis. The PPARγ agonists 15-deoxy-prostaglandin-J(2), ciglitazone, and pioglitazone reduced intimal expansion, intimal infiltration of CD45RO(+) memory T cells, and plasma levels of inflammatory cytokines. The PPARγ antagonist GW9662 reversed the protective effects of PPARγ agonists, confirming the involvement of PPARγ-mediated pathways. In vitro, pioglitazone inhibited both alloantigen-induced proliferation and superantigen-induced transendothelial migration of memory T cells, indicating the potential mechanisms of PPARγ effects. CONCLUSION: Our results suggest that PPARγ agonists inhibit allogeneic human memory T cell responses and may be useful for the treatment of vascular graft rejection.


Subject(s)
Arteries/immunology , Arteries/transplantation , Graft Rejection/immunology , Hypoglycemic Agents/pharmacology , PPAR gamma/agonists , Prostaglandin D2/analogs & derivatives , T-Lymphocytes/immunology , Thiazolidinediones/pharmacology , Adoptive Transfer , Anilides/pharmacology , Animals , Arteries/pathology , Cell Movement/drug effects , Cell Movement/immunology , Cell Proliferation/drug effects , Cytokines/immunology , Graft Rejection/drug therapy , Graft Rejection/pathology , Humans , Immunologic Memory/drug effects , Immunologic Memory/immunology , Isoantigens/immunology , Mice , Mice, SCID , PPAR gamma/antagonists & inhibitors , PPAR gamma/immunology , Pioglitazone , Prostaglandin D2/pharmacology , Superantigens/pharmacology , T-Lymphocytes/pathology , T-Lymphocytes/transplantation , Transplantation, Heterologous , Transplantation, Homologous
5.
Transplantation ; 89(11): 1347-53, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20216481

ABSTRACT

BACKGROUND: The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection. METHODS: Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure. RESULTS: Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year. CONCLUSIONS: In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.


Subject(s)
Graft Rejection/epidemiology , Kidney Transplantation/adverse effects , Pancreas Transplantation/physiology , Treatment Failure , Adult , Antilymphocyte Serum/therapeutic use , Body Weight , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/epidemiology , Female , Glomerular Filtration Rate , Glycated Hemoglobin/metabolism , Humans , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/mortality , Kidney Transplantation/physiology , Male , Middle Aged , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/therapeutic use , Predictive Value of Tests , Proteinuria/diagnosis , Proteinuria/epidemiology , Renal Replacement Therapy , Risk Assessment , Time Factors , Treatment Outcome
6.
Transplantation ; 88(8): 1010-8, 2009 Oct 27.
Article in English | MEDLINE | ID: mdl-19855247

ABSTRACT

BACKGROUND.: Sirolimus (SRL) is an important component of clinical immunosuppression in renal transplantation, but few international studies have examined how this agent is used in routine practice. METHODS.: Within a large prospective pharmacoepidemiological study, 718 de novo renal graft recipients treated with SRL in 65 centers in 10 countries were monitored for up to 5 years posttransplant to compare the principal outcomes and adverse effects by treatment regimen. RESULTS.: Principal treatment regimens were SRL without a calcineurin inhibitor (33%), SRL+cyclosporine A (CsA) (33%), and SRL+tacrolimus (TAC) (34%); 18% of subjects discontinued SRL, 124/718 (17%) developed biopsy-confirmed acute rejection (BCAR), 64/718 (9%) lost their graft, and 50/718 (7%) died during follow-up. Calculated creatinine clearance was 66+/-26 mL/min at 2 years. The most common adverse events were hypertension, hyperlipidemia, anemia, urinary tract infections, and diabetes. BCAR was significantly lower in subjects receiving SRL+TAC (hazard ratio [HR] 0.46, P=0.009) but not significantly lower in those receiving SRL+CsA (HR 0.62, P=0.102) compared with SRL without a calcineurin inhibitor. Graft loss or death did not significantly differ between treatment groups but were associated, respectively, with deceased donor grafts (HR 3.33, P<0.001) and increased age (HR 1.04, P<0.001). No improvement was observed in patients receiving mycophenolate mofetil in any treatment combination (HR 0.80, P=0.438 for BCAR; HR 0.93, P=0.849 for graft loss; and HR 0.75, P=0.531 for death). CONCLUSIONS.: SRL is most commonly used in combination with mycophenolate mofetil, CsA, or TAC. BCAR was least common in subjects receiving SRL+TAC, but other outcomes seemed comparable between the treatment regimens in routine practice.


Subject(s)
Kidney Transplantation/immunology , Sirolimus/therapeutic use , Tacrolimus/therapeutic use , Algorithms , Anemia/chemically induced , Cohort Studies , Creatinine/metabolism , Drug Therapy, Combination , Graft Rejection/epidemiology , Humans , Hyperlipidemias/chemically induced , Hypertension/chemically induced , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/mortality , Kidney Transplantation/physiology , Longitudinal Studies , Observer Variation , Prospective Studies , Sirolimus/adverse effects , Urinary Tract Infections/chemically induced
7.
Transplantation ; 87(2): 189-97, 2009 Jan 27.
Article in English | MEDLINE | ID: mdl-19155972

ABSTRACT

BACKGROUND: Nearly half of all infiltrating leukocytes in rejecting human allografts are macrophages, yet, in comparison with T cells, much less is known about the contribution of this cell type to rejection. Our laboratory has previously described models of rejection of human skin or artery grafts in immunodeficient mouse hosts mediated by adoptively transferred allogeneic T cells. However, mature human monocyte/macrophages have consistently failed to engraft in these animals. Here, we describe the introduction of human CD68+ macrophages into irradiated immunodeficient mice by transplantation of enriched CD34+ hematopoietic stem-cells isolated from peripheral blood of G-colony-stimulating factor pretreated adults. METHODS: We investigated strains of immunodeficient mice bearing human tissue grafts (skin and artery) inoculated with 1 x 10(6) human CD34+ adult hematopoietic stem cells, peripheral blood monuclear cells autologous to the CD34 donor, or both for human cell engraftment. RESULTS: In the absence of T cells, CD68+ CD14+ macrophages infiltrate allogeneic human skin but produce little injury or thrombosis. Both responses are enhanced when combined with adoptive transfer of T cells autologous to the hematopoietic stem cells as exemplified by the induction of the macrophage activation marker CD163. CD68+ macrophages also infiltrate allogeneic arterial interposition grafts, producing intimal expansion and calcification in the absence of T cells. CONCLUSIONS: These new models may be used to study the role of human macrophages in transplant rejection and other pathologies in vivo.


Subject(s)
Adult Stem Cells/immunology , Arteries/immunology , Arteries/transplantation , Graft Rejection/immunology , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/immunology , Macrophages/immunology , Skin Transplantation/immunology , Skin/immunology , Adoptive Transfer , Animals , Antigens, CD/analysis , Antigens, CD34/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Arteries/pathology , Disease Models, Animal , Graft Rejection/pathology , Humans , Interleukin Receptor Common gamma Subunit/genetics , Interleukin Receptor Common gamma Subunit/immunology , Lipopolysaccharide Receptors/analysis , Mice , Mice, Inbred NOD , Mice, Knockout , Mice, SCID , Receptors, Cell Surface/analysis , Skin/pathology , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Transplantation, Homologous , Whole-Body Irradiation
8.
Transplantation ; 86(5): 719-27, 2008 Sep 15.
Article in English | MEDLINE | ID: mdl-18791454

ABSTRACT

BACKGROUND: Graft arteriosclerosis (GA) is an important factor limiting long-term outcomes after organ transplantation. We have used a chimeric humanized mouse system to model this arteriopathy in human vessels, and found that the morphologic and functional changes of experimental GA are interferon (IFN)-gamma dependent. This study evaluated whether 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, described as inhibitors of IFN-gamma production, affect GA in our model. METHODS: C.B.-17 severe combined immunodeficiency-beige mice were transplanted with human artery segments as aortic interposition grafts and inoculated with allogeneic human peripheral blood mononuclear cells (PBMCs) or replication-deficient adenovirus encoding human IFN-gamma. Transplant arteries were analyzed from recipients treated with vehicle vs. atorvastatin or simvastatin at different doses. The effects of statins on T-cell alloresponses to vascular endothelial cells were also investigated in vitro. RESULTS: Graft arteriosclerosis-like arteriopathy induced by PBMCs was reduced by atorvastatin at 30 mg/kg/day or simvastatin at 100 mg/kg/day that correlated with decreased graft-infiltrating CD3+ T cells. Circulating IFN-gamma was also reduced, as were graft IFN-gamma and IFN-gamma-inducible chemokine transcripts and graft human leukocyte antigen-DR expression. Graft arteriosclerosis directly induced by human IFN-gamma in the absence of human PBMCs was also reduced by atorvastatin, but only at the highest dose of 100 mg/kg/day. Finally, atorvastatin decreased the clonal expansion and production of interleukin-2, but not IFN-gamma, by human CD4+ T cells in response to allogeneic endothelial cells in coculture. CONCLUSIONS: Our results suggest that a benefit of statin administration in transplantation may include amelioration of GA primarily by inhibiting alloreactive T-cell accumulation and consequent IFN-gamma production and secondarily through suppression of the arterial response to IFN-gamma.


Subject(s)
Heptanoic Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Interferon-gamma/biosynthesis , Leukocytes, Mononuclear/immunology , Pyrroles/therapeutic use , Simvastatin/therapeutic use , T-Lymphocytes/immunology , Adult , Animals , Arteries/transplantation , Atorvastatin , Flow Cytometry , Humans , Interferon-gamma/antagonists & inhibitors , Lymphocyte Transfusion , Mice , Mice, SCID , T-Lymphocytes/drug effects , Transplantation, Heterologous/immunology , Transplantation, Homologous
9.
Transplantation ; 83(11): 1501-5, 2007 Jun 15.
Article in English | MEDLINE | ID: mdl-17565324

ABSTRACT

Vascular remodeling rather than intimal thickening is the most important determinant of luminal loss in cardiac graft arteriosclerosis. The impact of donor-transmitted atherosclerotic lesions on alloimmune-mediated arterial injury in an experimental setting is not known. We investigated this issue in a chimeric model of human coronary artery grafts to immunodeficient mouse recipients reconstituted with allogeneic human peripheral blood mononuclear cells. Rejecting grafts demonstrated robust intimal expansion, outward vascular remodeling, and variable lumen loss. There was no significant relationship between preexistent atherosclerosis, gender, and age of the artery donors vs. the degree of alloimmune-induced changes in vessel morphology. Our experimental findings, in a system without the potentially confounding variable of immunosuppressive drugs, are in agreement with the majority of clinical studies that alloimmune-mediated intimal injury and vascular remodeling is independent of preexisting coronary atherosclerosis. Our results support the concept of extending the criteria for organ donors to include modest coronary atherosclerosis.


Subject(s)
Coronary Artery Disease/physiopathology , Coronary Vessels/physiopathology , Coronary Vessels/transplantation , Mice, SCID , Transplantation Immunology , Aged , Animals , Coronary Artery Disease/pathology , Coronary Vessels/immunology , Coronary Vessels/pathology , Female , Graft Rejection/pathology , Humans , Male , Mice , Middle Aged , Transplantation Chimera , Transplantation, Heterologous
12.
Transplantation ; 81(4): 559-66, 2006 Feb 27.
Article in English | MEDLINE | ID: mdl-16495804

ABSTRACT

BACKGROUND: Chronic allograft dysfunction may result from arterial injury, manifest as transplant arteriosclerosis (TA). This represents an important factor limiting long-term outcomes after heart and kidney transplantation; a relationship between acute allograft arterial injury and TA has been suggested. We have used SCID/bg mice bearing transplanted human artery, inoculated with allogeneic human PBMC to study arteriopathy in human vessels. Earlier work demonstrated arteriopathy similar to that observed clinically, and identified interferon-gamma as a mediator of the process. This study evaluated whether sirolimus (SRL), with cyclosporine A (CsA) or alone, affects TA, and examined possible mechanisms of action. METHODS: CB17/SCID/bg mice were transplanted with human arteries replacing the abdominal aorta; reconstituted with allogeneic human PBMC. Controls received vehicle alone for comparison with mice given CsA (5 mg/kg/d), SRL (0.1 or 0.5 mg/kg/d), or CsA (5 mg/kg/d) plus SRL (0.1 mg/kg/d). Transplant arteries were examined 28 days later by histology and immunohistochemistry; circulating human interferon-gamma was evaluated by ELISA, and intragraft interferon-gamma mRNA by qRT-PCR. RESULTS: The characteristic TA was modestly reduced by CsA or low-dose SRL, but eliminated by combination CsA plus SRL or higher dose SRL alone. Circulating interferon-gamma was reduced by CsA, but inhibition was dramatic with SRL alone or combined with CsA. Intragraft interferon-gamma and HLA-DR expression were moderately reduced by CsA or SRL, and eliminated with combined CsA plus SRL. CONCLUSIONS: SRL plus CsA prevented allograft arteriopathy, correlating with suppression of intragraft interferon-gamma, suggesting that SRL effects may result from anti-inflammatory consequences from inhibiting interferon-gamma.


Subject(s)
Arteries/transplantation , Cyclosporine/therapeutic use , Interferon-gamma/physiology , Sirolimus/therapeutic use , Transplantation, Homologous/pathology , Animals , Arteries/pathology , Humans , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Interferon-gamma/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/physiology , Mice , Mice, SCID , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Transplantation, Heterologous/pathology
13.
Nephrol Dial Transplant ; 21(5): 1389-94, 2006 May.
Article in English | MEDLINE | ID: mdl-16431893

ABSTRACT

BACKGROUND: Blockade of the renin-angiotensin-aldosterone system in the early post-transplant period remains controversial. Angiotensin II-receptor blockers (ARB) have many benefits to the patient with chronic kidney disease and these benefits may also apply to the renal transplant recipient (RTR). Additionally, there are theoretical benefits of ARB use in RTR. This study was designed to investigate the safety of early ARB use after renal transplantation. METHODS: RTR with serum creatinine levels <3.0 mg/dl were randomized to receive either ARB (n = 29) or calcium-channel blocker (CCB; n = 27) as initial therapy for post-transplant hypertension. Differences in potassium, creatinine and haemoglobin concentrations were compared at baseline, 3, 6 and 12 months after transplantation. RESULTS: Withdrawal from the assigned treatment was high: 12 in the ARB group (due to hyperkalaemia in six) and 17 in the CCB group (due to intractable oedema in seven and post-transplant erythrocytosis requiring an angiotensin-converting enzyme inhibitor in seven). There were no differences in blood pressure, haemoglobin or creatinine concentration at any time-points. Mean potassium concentrations were only slightly higher in the ARB vs CCB group (range: 4.2-4.3 vs 3.7-3.8 mEq/l, respectively, but clinically significant) and the number of patients with potassium values >6.0 mEq/l was higher in ARB (n = 7) vs CCB (n = 1). CONCLUSIONS: These data suggest that hyperkalaemia is the major complication that occurs with the use of ARB in the immediate post-transplant period. ARB use does not affect renal function or complicate the post-transplant management of RTR. Other than reducing the incidence of post-transplant erythrocytosis, ARB use does not cause an excess incidence of anaemia. Strategies to reduce the risk of hyperkalaemia may allow increased use of ARB immediately after kidney transplantation.


Subject(s)
Amlodipine/administration & dosage , Hypertension/drug therapy , Kidney Transplantation/adverse effects , Losartan/administration & dosage , Adult , Aged , Blood Pressure Determination , Chi-Square Distribution , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Hypertension/etiology , Hypertension/physiopathology , Kidney Failure, Chronic/diagnosis , Kidney Failure, Chronic/surgery , Kidney Transplantation/methods , Male , Middle Aged , Probability , Risk Assessment , Severity of Illness Index , Treatment Outcome
14.
Transplantation ; 80(2): 244-52, 2005 Jul 27.
Article in English | MEDLINE | ID: mdl-16041270

ABSTRACT

BACKGROUND: This 36-month, randomized, parallel-group study compared safety and efficacy of two doses of everolimus with mycophenolate mofetil (MMF) in de novo renal-transplant recipients. METHODS: Renal-allograft recipients received 1.5 mg/day or 3 mg/day of everolimus or 2 g/day of MMF, plus full-dose cyclosporine (CsA) and corticosteroids after randomization. For at least their first year, patients received study medication according to a double-blinded, double-dummy design. Concerns over nephrotoxicity led to a protocol amendment to an open-label design with reduced CsA troughs. RESULTS: Incidences of primary efficacy failure at 36 months (biopsy-proven acute rejection, graft loss, death, or loss to follow-up) were everolimus 1.5 mg/day, 33.7% (65/193); everolimus 3 mg/day, 34.0% (66/194); and MMF, 31.1% (61/196) (P=0.810). Antibody-treated acute rejection at 36 months was significantly lower with everolimus 1.5 mg (9.8%) than MMF (18.4%, P=0.014). Discontinuation for adverse events was more frequent with everolimus and hemolytic uremic syndrome, lymphoproliferative disease, and proteinuria, and higher serum creatinine occurred at increased frequency relative to the MMF arm. Creatinine levels in the everolimus arms were stable in follow-up: the mean rise in creatinine over the first 6 months of the open-label phase was 3 micromol/L or greater with everolimus and 7 micromol/L with MMF. However, serum creatinine levels were lower in the MMF group throughout. Death and graft loss were higher in the everolimus arms (not significant). CONCLUSIONS: As part of triple-drug immunosuppression, everolimus (1.5 or 3 mg/day) was as efficacious as MMF, although the side-effect profile featured increased adverse events. Nephrotoxicity/calcineurin-inhibitor-related adverse events will require judicious lowering of CsA exposure with monitoring of everolimus troughs.


Subject(s)
Graft Rejection/prevention & control , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , Mycophenolic Acid/analogs & derivatives , Sirolimus/analogs & derivatives , Adolescent , Adult , Aged , Drug Therapy, Combination , Everolimus , Female , Humans , Male , Middle Aged , Mycophenolic Acid/therapeutic use , Safety , Sirolimus/therapeutic use , Tissue Donors/statistics & numerical data
15.
Clin Transplant ; 19(2): 145-52, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15740547

ABSTRACT

The aims of the current study were to determine whether therapeutic drug monitoring (TDM) might benefit kidney transplant recipients receiving everolimus, and to establish dosage recommendations when everolimus is used in combination with cyclosporine and corticosteroids. The analysis was based on data from 779 patients enrolled in two 12-month trials. Everolimus trough concentrations >/=3 ng/mL were associated with a reduced incidence in biopsy-proven acute rejection (BPAR) in the first month (p = 0.0001) and the first 6 months (p = 0.0001), and reduced graft loss compared with lower concentrations (4% vs. 20%, respectively). By contrast, cyclosporine in the standard concentration range had no impact on BPAR within the same timeframes. Most patients receiving everolimus 1.5 or 3 mg/d achieved trough concentrations above the therapeutic threshold of 3 ng/mL, regardless of reductions in cyclosporine dose. TDM simulation showed that just two dose adjustments would achieve median everolimus trough values >/=3 ng/mL in 95% of patients during the first 6 months. This investigation indicates that improved efficacy is likely when TDM is considered as an integral component of the immunosuppressive strategy of everolimus.


Subject(s)
Drug Monitoring , Immunosuppressive Agents/therapeutic use , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Sirolimus/analogs & derivatives , Sirolimus/therapeutic use , Biopsy , Cyclosporine/administration & dosage , Cyclosporine/blood , Cyclosporine/therapeutic use , Double-Blind Method , Everolimus , Follow-Up Studies , Graft Rejection/prevention & control , Graft Survival , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/therapeutic use , Prednisolone/administration & dosage , Prednisolone/therapeutic use , Safety , Sirolimus/administration & dosage , Sirolimus/blood , Time Factors , Treatment Outcome
16.
Am J Transplant ; 5(1): 157-66, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15636625

ABSTRACT

This study presents the first prospective multicenter study assessing sirolimus-based immunosuppression with early (4-day) corticosteroid withdrawal (CSWD) in renal transplantation. Immunosuppression included: anti-IL-2 receptor antibody and tacrolimus/sirolimus. Inclusion criteria included adult primary recipients. Exclusion criteria included: (i) African Americans, (ii) current PRA >50%, (iii) multiple organ transplants, (iv) WBC < 3000 cells/microL and (v) fasting hypercholesterolemia/hypertriglyceridemia. The primary endpoints were acute rejection and the proportion of patients off corticosteroids. Seventy-seven patients were enrolled: mean age of 49.7 +/- 12 years. Transplants included: cadaveric (26%) and living donor (74%). Patient and graft survival were 100%. Biopsy proven acute rejection occurred in 13%; presumptive rejection in 10.5%. Banff grades included: IA (seven patients), IB (one patient), IIA (one patient) and IIB (one patient). Renal function at 1 year: serum creatinine (1.18 +/- 0.06 mg/dL). Mean weight gain was minimal at 1 year: 3 +/- 2 kg/patient. Mild increases in total, LDL and HDL cholesterol were observed and new antilipid agent use occurred in 26 patients. In conclusion, early CSWD under tacrolimus/sirolimus-based immunosuppression in selected, low-risk renal transplant recipients provides: (i) excellent patient and graft survival, (ii) good renal function, (iii) reduced hyperlipidemia and antilipid agent use and (iv) low acute rejection rates.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/methods , Recombinant Fusion Proteins/therapeutic use , Sirolimus/therapeutic use , Steroids/therapeutic use , Tacrolimus/therapeutic use , Adrenal Cortex Hormones/therapeutic use , Adult , Basiliximab , Biopsy , Blood Pressure , Body Weight , Cadaver , Cardiovascular System , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Creatinine/blood , Female , Graft Rejection , Graft Survival , Humans , Immunosuppressive Agents/administration & dosage , Infections/etiology , Living Donors , Male , Middle Aged , Pilot Projects , Risk Factors , Time Factors , Treatment Outcome
17.
Microsurgery ; 24(6): 465-7, 2004.
Article in English | MEDLINE | ID: mdl-15378574

ABSTRACT

Removal of a transplanted organ from its original recipient and retransplanting it into a new host is an important method to study the role of the graft in the rejection process. Here we describe a novel technique of heart retransplantation in the mouse. In this technique, a primarily vascularized heart graft is anastomosed to the abdominal aorta and inferior vena cava of a syngeneic or immunodeficient allogeneic mouse, using standard techniques. Either 10 or 70 days later, the same graft is retransplanted into the abdomen of a second mouse by end-to-side anastomosis of the donor (first recipient) aortic and inferior vena cava's cuffs to the second recipient's abdominal aorta and inferior vena cava, respectively. A greater than 90% success rate was achieved by using this microsurgical technique. This method should be useful for studying intragraft factors, such as ischemia-reperfusion injury and donor antigen-presenting cells, on the outcomes of transplantations.


Subject(s)
Heart Transplantation/methods , Transplantation, Heterotopic/methods , Anastomosis, Surgical , Animals , Antigen-Presenting Cells/pathology , Aorta, Abdominal/surgery , Aorta, Abdominal/transplantation , Female , Graft Rejection/etiology , Graft Rejection/immunology , Graft Survival , Heart Transplantation/immunology , Mice , Mice, Inbred BALB C , Mice, Mutant Strains , Microsurgery , Myocardial Reperfusion Injury/etiology , Splenectomy , Time Factors , Transplantation, Homologous , Transplantation, Isogeneic , Vena Cava, Inferior/surgery , Vena Cava, Inferior/transplantation
18.
J Clin Invest ; 114(6): 846-56, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15372109

ABSTRACT

Allograft vascular dysfunction predisposes to arteriosclerosis and graft loss. We examined how dysfunction develops in transplanted human arteries in response to circulating allogeneic T cells in vivo using immunodeficient murine hosts. Within 7-9 days, transplanted arteries developed endothelial cell (EC) dysfunction but remained sensitive to exogenous NO. By 2 weeks, the grafts developed impaired contractility and desensitization to NO, both signs of VSMC dysfunction. These T cell-dependent changes correlated with loss of eNOS and expression of iNOS--the latter predominantly within infiltrating T cells. Neutralizing IFN-gamma completely prevented both vascular dysfunction and changes in NOS expression; neutralizing TNF reduced IFN-gamma production and partially prevented dysfunction. Inhibiting iNOS partially preserved responses to NO at 2 weeks and reduced graft intimal expansion after 4 weeks in vivo. In vitro, memory CD4+ T cells acted on allogeneic cultured ECs to reduce eNOS activity and expression of protein and mRNA. These effects required T cell activation by class II MHC antigens and costimulators (principally lymphocyte function-associated antigen-3, or LFA-3) on the ECs and were mediated by production of soluble mediators including IFN-gamma and TNF. We conclude that IFN-gamma is a central mediator of vascular dysfunction and, through dysregulation of NOS expression, links early dysfunction with late arteriosclerosis.


Subject(s)
Arteries/transplantation , Endothelium, Vascular/pathology , Interferon-gamma/physiology , Nitric Oxide Synthase/genetics , T-Lymphocytes/immunology , Transplantation, Homologous/physiology , Animals , Arteries/immunology , Arteriosclerosis/immunology , CD4-Positive T-Lymphocytes/immunology , Endothelium, Vascular/immunology , Humans , Mice , Mice, SCID , Nitric Oxide Synthase Type II , Transplantation, Heterologous/immunology , Transplantation, Heterologous/pathology , Transplantation, Homologous/immunology
20.
FASEB J ; 18(3): 606-8, 2004 Mar.
Article in English | MEDLINE | ID: mdl-14734640

ABSTRACT

Vascular remodeling (change in vessel diameter) rather than intimal hyperplasia is the most important predictor of luminal loss in immune-mediated arterial injury, yet little is known about its mechanisms. Here, we show that outward vascular remodeling and intimal thickening, two manifestations of arteriosclerosis with opposing effects on luminal size, result from immune effector mechanisms that are T-cell dependent and interferon (IFN)-gamma mediated. In our in vivo model of human coronary artery injury by allogeneic peripheral blood mononuclear cells, both processes occur concurrently and are characterized by T-cell infiltrates with a predominantly IFN-gamma-producing cytokine profile. Neutralization of IFN-gamma inhibits the arterial and intimal expansion, whereas administration of IFN-gamma enhances these effects. The nonredundant role of IFN-gamma in T-cell-dependent remodeling of human coronary arteries demonstrated here presents a new therapeutic target for preservation of vessel lumen in arteriosclerosis.


Subject(s)
Coronary Vessels/immunology , Graft Rejection/immunology , Interferon-gamma/physiology , T-Lymphocyte Subsets/immunology , Adoptive Transfer , Animals , Aorta, Abdominal/surgery , Coronary Vessels/pathology , Coronary Vessels/transplantation , Female , Gene Expression Profiling , Humans , Immunophenotyping , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/pharmacology , Mice , Mice, Mutant Strains , Mice, SCID , Recombinant Proteins , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocyte Subsets/metabolism , T-Lymphocyte Subsets/transplantation , Transplantation Chimera , Transplantation, Heterologous , Tunica Intima/pathology
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