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Results for “Allografts”

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At least 19 recordsLinked to original sources

PubMed1985

Drug-induced tolerance to allografts in mice II. Tolerance to tumor allografts of large doses associated with rejection of skin allografts and tumor allografts of small doses.

Antigen-specific tolerance to tumor allografts in mice was obtained by stimulation with allogeneic spleen cell antigens and treatment with cyclophosphamide (CY) 2 days later in various strain combinations between donor mice of spleen cell antigens and recipients. In such tolerant mice, skin allografts were rejected in various combinations of the donor-recipient. Furthermore, some of the tolerant mice showed accelerated rejection of tumor allografts of small doses, even though they allowed progressive growth of the same tumor allografts of large doses. Our results suggest that the rejection of tumor allografts of large doses may depend upon a mechanism that is distinct, qualitatively or quantitatively, from that one responsible for the rejection of tumor allografts of small doses and skin allografts. One of the most important properties of lymphocytes to separate these two different mechanisms may be a capacity of clonal expansion, namely, sensitivity to CY-induced tolerance of the lymphocytes mediating allograft rejection.

Animals↗

PubMed1999

Explanted cryopreserved allografts: a morphological and immunohistochemical comparison between arterial allografts and allograft heart valves from infants and adults.

OBJECTIVE: Life expectancy of cryopreserved allografts implanted in infants is different from those implanted in adults. A morphological study of explanted allograft heart valves was performed to determine the mechanism of deterioration and to compare cryopreserved arterial and heart valve allografts from adult patients with those explanted from infants. METHOD: Between 1987 and 1996, 209 cryopreserved allografts were implanted: 125 valved conduits or monocusps to reconstruct the right ventricular outflow tract in congenital heart disease, 50 allograft heart valves to treat native aortic and prosthetic aortic valve endocarditis and 34 cryopreserved arterial allografts to replace mycotic aortic aneurysms or infected aortic prosthetic grafts. Two months to 8 years after implantation, 23 heart valve allografts, 11 right-sided and 12 left-sided, and four arterial allografts had to be explanted for reasons such as degeneration, recurrent infection, aneurysm formation or rupture. Besides conventional staining, immunohistochemical detection of cell populations was performed as follows: CD45RO, CD3 and CD43 for T lymphocytes, CD20 for B lymphocytes, CD68 for macrophages, protein S100 for Langerhans-cells, vimentin for fibroblasts, alpha-actin for smooth muscle cells and factor VIII for endothelial cells. RESULTS: Explanted cryopreserved allografts were all fibrotic, acellular, non-vital and without endothelial cells. The fibrous tissue was preserved. T lymphocytes, indicating rejection, were found in all right-sided allografts from the paediatric population, but only in 9% of left-sided valves explanted from adults and in one of the four of arterial allografts. Macrophages and Langerhans-cells were found only in right-sided allografts from paediatric patients. CONCLUSION: Right-sided cryopreserved allografts from a paediatric population showed ongoing cellular rejection. By contrast, there was only a weak T-cell mediated rejection to adult heart valve and arterial allografts. Therefore, similar long-term results can be expected in adult arterial and heart valve allografts, whereas longevity of right-sided heart valve allograft in the paediatric age group seems endangered by cellular rejection.

Adolescent↗

PubMed2001

Allograft-allograft healing? Salvage of massive allografts after fracture.

Two cases are presented in which an allograft was inserted to salvage a previous allograft bone reconstruction that had followed resection for osteosarcoma. In each instance an allograft-allograft junction was created and, with time, healed. In the first case, a fracture of a distal femoral osteoarticular allograft was salvaged by adding a second allograft and a total knee arthroplasty. This construct preserved the majority of the allograft and allowed rapid rehabilitation. In the second case, an allograft arthrodesis of the knee was salvaged after fracture by replacing the distal portion of the fractured allograft with a new allograft. Again, an allograft-allograft junction was created and healed within 6 months. Allograft fractures pose challenging reconstructive problems. In these two cases, the addition of more allograft facilitated continued limb salvage and function.

Arthrodesis↗

PubMed1987

Cross-reactivity of organs in allograft rejection. Comparison of effect of thyroid allografts on established islet allografts.

The effect of allotransplantation of thyroid or islet allografts into rats with established islet allografts was studied to determine the cross-reactivity of the thyroid and islets in allograft rejection. Islets obtained from cultured neonatal rat (F344) pancreas explants were transplanted bilaterally underneath the kidney capsule of Wistar-Furth rats. After 21 days these allografts did not exhibit signs of rejection. Thyroid (half lobe) from either F344 or Brown Norway rats was transplanted underneath the capsule of the remaining kidney. Transplant of the thyroid from F344 rats resulted in immediate rejection of the islet transplant, whereas transplant of the thyroid from Brown Norway rats was without effect on the islet allograft. This indicates that the thyroid contains immunocompetent cells (cells that present antigen or induce recognition of antigen) that are capable of initiating rejection of established islet allografts. The cytotoxic T-lymphocytes that result are specific for the organ bearing the immunocompetent cells at time of transplantation.

Animals↗

PubMed1980

Morphological findings in duct-ligated pancreas grafts in the rat. An analysis of isografts, allografts, and long-standing allografts in hosts conditioned by previous spleen allograft.

The morphological findings of duct-ligated pancreas grafts in streptozotocin-induced diabetic hosts were studied using inbred AGUS and WAG rats with a major histocompatibility complex differences. AGUS to AGUS pancreas isografts survived indefinitely. Morphologically, islet tissue was partly dispersed and showed about 75% granulated beta cells. Fibrosis was minimal and inflammatory cells generally absent. WAG to AGUS allografts were quickly rejected and showed severe pancreatitis with a polymorphonuclear and mononuclear infiltrate. Islet destruction lagged behind that of exocrine tissue and vascular thrombosis was a late event. In the last group, AGUS recipients first received WAG spleen allografts which survived spontaneously. There to 5 months later they were removed and WAG pancreas allografts inserted. Sixty-eight percent of these pancreas allografts survived. Four to 10 months later they were characterized by severe dense fibrosis surrounding islet tissue. Capillaries were always present between islet cells, about 75% of which showed beta granules. A mild to moderate mononuclear cell infiltrate and vascular intimal proliferation were also part of the picture. We conclude that pancreatitis after duct-ligated pancreas allografts is not a sequel of duct ligation but results from rejection and can be prevented with adequate immunosuppression. Fibrosis does not have a detrimental effect on islet cell function as a result of the feasibility of insulin secretion by beta cells into adjacent capillaries and thence to larger vessels traversing through the dense fibrosis.

Animals↗

PubMed2003

Immunogenicity of decellularized cryopreserved allografts in pediatric cardiac surgery: comparison with standard cryopreserved allografts.

BACKGROUND: Recognition of the immunogenicity of standard cryopreserved allografts has led to the development of new decellularized allografts (CryoValve SG; CryoLife, Inc, Kennesaw, Ga). This preliminary study examined the HLA antibody response to these decellularized allografts and compared it with the response to standard allograft material. METHODS: We prospectively measured the frequency of panel-reactive HLA class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DR/DQ) alloantibodies in 14 children (age 8.5 +/- 7.9 years) receiving decellularized, cryopreserved allografts, including 6 undergoing allograft patch insertion and 8 with a valved pulmonary allograft. We compared them with 20 historical control subjects (age 1.7 +/- 2.4 years) undergoing implantation of standard cryopreserved allografts, 8 with valves and 12 with allograft patch. All patients had panel-reactive antibody levels measured before and at 1, 3, and 12 months after the operation. HLA class I and class II panel-reactive antibody levels were determined with a sensitive flow cytometry technique. RESULTS: We found panel-reactive antibody levels in decellularized allografts to be elevated slightly from preoperative levels for both class I and class II antibodies at 1, 3, and 12 months (P >.05). The panel-reactive antibody level for both class I and class II antibodies were significantly lower for decellularized allografts as compared to standard allografts. Functionally, the allografts were similar with decellularized valved grafts showing a peak echo-determined systolic gradient of 13 +/- 15 mm Hg at 8 +/- 2.6 months postoperatively as compared to a gradient of 24 +/- 18 mm Hg measured 12 +/- 6 months postoperatively in standard allografts (P =.11). CONCLUSIONS: Decellularized grafts elicited significantly lower levels of class I and class II HLA antibody formation at 1, 3, and 12 months after implantation than did standard cryopreserved allografts. Early hemodynamic function of decellularized grafts was similar to that of standard cryopreserved allograft valves. Further experience is necessary to determine whether the reduced immunogenicity of decellularized allografts will truly allow tissue ingrowth and improved long-term durability in patients.

Adolescent↗

PubMed1997

Intramedullary, antibiotic-loaded cemented, massive allografts for skeletal reconstruction. 26 cases compared with 19 uncemented allografts.

We compared the outcomes of 26 intramedullary cemented massive allografts with 19 allografts without cementation; all allografts were used for reconstruction after excision of bone sarcomas. In the cementation group, 12 allografts were used as osteochondral grafts (proximal humerus 4, proximal tibia 4, and distal femur 4), 7 as intercalary diaphyseal allografts of the femur, and 7 for a knee arthrodesis. In the uncemented allografts, 3 allografts were used as osteochondral grafts (proximal humerus 2, proximal tibia 1), 2 as intercalary diaphyseal allograft of the femur, and 14 for a knee arthrodesis. The average length of follow-up was 40 (25-60) months. 14 of 26 cemented allografts had an excellent (osteotomy line: not visible) or good (fusion > or = 75% of the cortical thickness) healing of the junction site. Infection developed in 1 allograft. Fracture occurred in 4 of 12 cemented osteochondral allografts due to a subchondral collapse (all in the proximal tibia). Fractures at the junction site in the lower extremity developed in 4 of 22 cemented allografts. In 19 allografts without cementation, 11 had excellent or good healing of the junction. Late infection developed in 4 allografts, fracture of the allograft in 3 cases, and junction fracture in 3 of 17 patients with reconstruction of the lower extremity. Intramedullary graft cementation seems to reduce the fracture and infection rates.

Adolescent↗

PubMed2002

Mechanisms of chronic renal allograft rejection. II. Progressive allograft glomerulopathy in miniature swine.

We have reported that in thymectomized miniature swine treated with a 12-day course of cyclosporin A that major histocompatibility complex class I-mismatched renal allografts either progress to chronic rejection (progression group; n = 4) or tolerance after acute rejection (recovery group; n = 4). Two types of glomerulopathies, termed acute and chronic allograft glomerulopathy, occur in allografts in this model. Morphological and immunohistochemical studies were performed on serial renal biopsies from both groups to examine the pathogenic mechanisms of acute and chronic allograft glomerulopathy. In acute rejection, acute allograft glomerulopathy developed in both groups by Day 18, with antibody deposition and T cell and macrophage infiltration. In situ DNA nick end-labeling (TUNEL)+ injured glomerular endothelial cells appeared from the early phase, followed by destruction of the glomerular capillary network with segmental mesangiolysis. Thereafter, in the progression group, acute allograft glomerulopathy progressed to chronic allograft glomerulopathy during the development of chronic rejection. This process was associated with persistent T cell and macrophage infiltration, antibody deposition, and TUNEL+ glomerular endothelial injury in the glomeruli. Impaired capillary repair, mesangial cell proliferation, and activation were still noted at Day 100, together with accumulation of mesangial matrix and duplication of glomerular basement membrane. In contrast, in the recovery group, acute allograft glomerulopathy recovered by Day 100, associated with the resolution of cellular infiltration and reduction of antibody deposition. We conclude that the acute and persistent cell- and antibody-mediated rejection against glomerular endothelial cells is the key pathogenic determinant of acute allograft glomerulopathy and progression toward chronic allograft glomerulopathy. Impaired capillary repair and phenotypic change of endothelial and mesangial cells also contribute to the development of chronic allograft glomerulopathy. With the development of tolerance, substantial recovery of acute allograft glomerulopathy can occur after the resolution of glomerular inflammation.

Acute Disease↗

PubMed1998

Patterns of allosensitization in allograft recipients: long-term cardiac allograft acceptance is associated with active alloantibody production in conjunction with active inhibition of alloreactive delayed-type hypersensitivity.

BACKGROUND: The immunologic characteristics of experimental allograft acceptance remain ill-defined. This study evaluates humoral and cell-mediated immunity in transiently immunosuppressed mice that have accepted cardiac allografts. METHODS: DBA/2-->C57BL/6 heterotopic cardiac allograft recipients were immunosuppressed with either GK1.5 monoclonal antibody or gallium nitrate and monitored for donor-reactive delayed-type hypersensitivity (DTH) assessed by ear challenge and for alloantibody production detected by flow cytometry. RESULTS: Cardiac allograft function continued for >90 days in approximately 50% of GK1.5-treated and 97% of gallium nitrate-treated transplant recipients. All nonsuppressed recipients lost graft function within 7 to 10 days. Among mice that accepted allografts, donor-reactive IgG was produced by about 50% of GK1.5 monoclonal antibody-treated mice and 80% of gallium nitrate-treated mice. None of the these mice exhibited donor-reactive DTH responses, and all could down-regulate third-party DTH responses in a donor alloantigen-dependent manner. This down-regulation is not found in nonsuppressed allograft recipients or in naive mice. Importantly, transfer into SCID mice of splenocytes from mice that accepted allografts, but not naive splenocytes, provided them with a similar ability to accept cardiac allografts, even if the grafts co-expressed third-party alloantigens. CONCLUSIONS: IgG alloantibody production by murine cardiac allograft recipients is not a precise indicator of allosensitization leading to either cardiac allograft rejection or acceptance. However, expression of alloreactive DTH is a reliable indicator of allosensitization leading to acute rejection, and the absence of DTH in association with active DTH down-regulatory mechanisms is a reliable indicator of allograft acceptance in this experimental model. Thus, DTH analysis may hold more promise than alloantibody detection for clinical assessment of posttransplant immune status.

Animals↗

PubMed2005

Superior durability of SynerGraft pulmonary allografts compared with standard cryopreserved allografts.

BACKGROUND: The ideal pulmonary valve replacement for children and adolescents remains elusive. Although favored by many surgeons, the cryopreserved pulmonary allograft tends to become rapidly incompetent and elicits an immune response. The SynerGraft process (Cryolife Inc, Kennesaw, GA) decellularizes a pulmonary allograft, leaving a scaffold of connective tissue. These grafts have been shown to decrease immune reactivity and become populated with host cells. Although theoretically these traits may improve durability, few data comparing SynerGraft-processed allografts (SynAs) (Cryolife Inc) with standard cryopreserved allografts are available. METHODS: A single institution review was performed for all SynAs implanted from their introduction in 2001 to January 2003. Twenty-six patients with SynAs and 26 age and diagnosis-matched controls receiving cryopreserved allografts were evaluated. Subjects were analyzed for demographics, survival, reintervention, and echocardiographic findings. RESULTS: There were no significant differences between groups in age, weight, valve diameter, orthotopic and heterotopic allograft position, or follow-up. On echocardiogram there was no difference in initial degree of allograft insufficiency or gradient. However, at mean follow-up of 19 +/- 13 months, SynAs were significantly less regurgitant than cryopreserved allografts (p = 0.017). Although all gradients were low, a significant difference between SynAs (7.6 +/- 14 mm Hg) and cryopreserved allografts (14.6 +/- 15.6 mm Hg; p = 0.012) had emerged. Survival was identical at 85% (22 of 26). Rates of reintervention were similar at 7% (2 of 26) for cryopreserved allografts and 3.8% (1 of 26) for SynAs (p = 0.98). CONCLUSIONS: At intermediate follow-up, the SynA demonstrated greater durability with less insufficiency and lower gradients. These characteristics are important to many patients with complex congenital heart disease; however, long-term effects on survival and reintervention remain unknown.

Case-Control Studies↗

PubMed2004

Low-dose aspirin therapy is associated with improved allograft function and prolonged allograft survival after kidney transplantation.

BACKGROUND: Aspirin treatment has an undoubted beneficial impact on the progression of cardiovascular diseases. We hypothesized that aspirin also protects allograft function and survival in the context of chronic renal allograft dysfunction, which displays decisive pathophysiologic features that are similar to those involved in atherogenesis. METHODS: A retrospective, multivariate analysis was performed to assess the effect of low-dose aspirin treatment (100 mg/day) on allograft function and survival of 830 renal transplant recipients. Allograft function was evaluated by serum creatinine levels, urine protein levels, and the presence of hematuria. RESULTS: Median allograft survival time was significantly longer in patients receiving low-dose aspirin therapy compared with patients receiving no aspirin treatment (n=205, 13.8 +/- 2.6 vs. 7.8 +/- 0.3 years, n=625; adjusted relative risk=0.443, 95% confidence interval [0.323-0.608], P<0.0001). Statin treatment and a recent time point of transplantation, reflecting the qualitative advances of the applied immunosuppressive therapy, were further positive determinants of renal allograft survival. The number of antihypertensive agents, representing the extent of hypertension, was a negative determinant of allograft survival. Transplant function was better preserved in aspirin-treated patients, who displayed a slower increase of serum creatinine and less proteinuria and hematuria during the observation period. The duration of aspirin treatment was positively associated with better allograft function. CONCLUSIONS: Low-dose aspirin therapy substantially improves renal allograft function and allograft survival. These findings suggest that aspirin should be considered to complement long-term posttransplant medical treatment regimens.

Adult↗

PubMed2001

Association of thrombospondin-1 and cardiac allograft vasculopathy in human cardiac allografts.

BACKGROUND: Despite the expression of angiogenic growth factors in transplanted hearts, neovessel formation appears scant. We therefore hypothesized that cardiac allografts contain endogenous inhibitors of angiogenesis. In particular, we tested the involvement in cardiac allografts of thrombospondin-1 (TSP-1), a matrix glycoprotein that inhibits angiogenesis and facilitates smooth muscle cell (SMC) proliferation. METHODS AND RESULTS: Levels of TSP-1 mRNA in endomyocardial biopsy samples of human cardiac allografts substantially exceeded those in normal hearts. The ratio of TSP to GAPDH mRNA determined with quantitative RT-PCR was 6.54+/-1.6 in cardiac allografts versus 0.26+/-0.02 (P:=0.001) in normal hearts. Analysis in sequential biopsies revealed a strong association between persistent elevation of TSP-1 in allografts and the development of cardiac allograft vasculopathy (CAV). The CAV score was 2.4+/-0.8 in patients with persistent TSP-1 elevation compared with 0.2+/-0.2 in patients without elevation (P:=0.001). Immunohistochemistry demonstrated intense expression of TSP-1 in cardiac allografts, predominantly in cardiac myocytes and neointimal SMCs. In vitro experiments demonstrated that T cells expressed TSP-1, acidic fibroblast growth factor, and vascular endothelial cell growth factor on allogeneic stimulation. Cytokines known to be elevated in cardiac allografts (interleukin-1beta, interferon-gamma, and tumor necrosis factor-alpha) induced TSP-1 in SMCs but inhibited TSP-1 in endothelial cells. CONCLUSIONS: Persistent elevation of TSP-1 in cardiac allografts correlates with the development of CAV. Allogeneic stimulation induces angiogenic growth factors and TSP-1 in T cells. Cytokines differentially regulate TSP-1 expression in SMCs versus endothelial cells. Increased levels of TSP-1 in human cardiac allografts may alter vascular responses to angiogenic growth factors by inhibiting angiogenesis and promoting SMC proliferation characteristic of CAV.

Blotting, Northern↗

PubMed1994

Acute cytomegalovirus infection induces a subendothelial inflammation (endothelialitis) in the allograft vascular wall. A possible linkage with enhanced allograft arteriosclerosis.

Clinical and experimental studies have established the accelerating role of cytomegalovirus (CMV) infection on cardiac allograft arteriosclerosis, ie, chronic rejection. We have investigated the mechanisms behind the interaction between CMV infection and chronic rejection. In the first part of the study, 762 endomyocardial biopsy specimens obtained from 47 heart allograft recipients were analyzed. Of these, 28 patients developed CMV infection during the first postoperative year. In 24 of 28 CMV patients, mononuclear inflammatory cells (endothelialitis) were seen in the subendothelium of small intramyocardial arterioles. In CMV-free recipients, only five of 19 had any subendothelial inflammation in the vascular structures P < 0.0001 when compared with CMV patients). The subendothelial inflammation demonstrated an intensive peak at the onset of CMV infection, subsiding slowly thereafter. Morphologically, the inflammatory cells in the subendothelium were small lymphocytes. Only few activated pyroninophilic lymphocytes were seen. Immunohistochemistry revealed that the lymphocytes were mostly T cells (UCHL1+). In the second part of the study, we investigated if a similar endothelialitis could be induced experimentally in allografted rats. We performed rat aortic allografts from the DA (AG-B4, RT1a) donors to the WF (AG-B2, RT1v) recipients and infected the recipients with 10(5) plaque-forming units of rat CMV Maastricht strain 1 day after transplantation. In rat CMV-infected aortic allografts, the frequency of subendothelial leukocyte common antigen (LCA, OX1) positive leukocytes, 1.7 +/- 0.1 (SEM) point score units, was significantly higher when compared to noninfected allografts, 0.8 +/- 0.1 point score units (P < 0.05), and they were most prominent in the intimal space during and following acute infection. During subsequent weeks, the LCA-positive leukocytes were replaced by alpha-actin-positive smooth muscle cells. Instead, most of the cells in intima of CMV-free grafted rats stained positively to alpha-actin from the beginning and were smooth muscle cells. Practically no leukocytes were seen. In rat CMV-infected aortic allografts most subendothelial inflammatory cells represented T cells (W3/25+) and cells of the monocyte/macrophage lineage (OX42+). In conclusion, acute CMV infection is associated with an subendothelial inflammation (endothelialitis) of allograft vascular structures both in human and in rat. Nonactivated T lymphocytes and monocytes predominate the inflammatory lesion in the subendothelium. The results suggest that the virus-linked vascular wall inflammation may play a role in the immune injury toward allograft vascular structures, particularly to endothelium, and thus contribute to allograft arteriosclerosis.

Acute Disease↗

PubMed2005

Effects of mycophenolate mofetil on cardiac allograft survival and cardiac allograft vasculopathy in miniature swine.

BACKGROUND: Chronic rejection, as manifested by cardiac allograft vasculopathy, remains the leading cause of late graft failure in heart transplant recipients. Despite recent clinical trials, the efficacy of mycophenolate mofetil in preventing human cardiac allograft vasculopathy remains controversial. We investigated whether mycophenolate mofetil would prevent cardiac allograft vasculopathy and prolong cardiac allograft survival in our well-established miniature swine model of heart transplantation. METHODS: Hearts disparate at the major histocompatibility complex class I locus were heterotopically transplanted into miniature swine recipients treated with a 12-day course of mycophenolate mofetil (n = 3) or cyclosporine A (n = 3). Allograft survival, acute rejection, and chronic rejection were monitored in the two groups. RESULTS: Hearts transplanted with 12 days of cyclosporine were rejected between 46 and 61 days, whereas two of the three hearts transplanted with mycophenolate mofetil remained beating beyond 120 days (p = 0.02). At necropsy, there was a 4.9% mean prevalence of cardiac allograft vasculopathy in the mycophenolate mofetil group as compared with 16.6% in the cyclosporine group (p = 0.03). Cardiac allograft rejection and vasculopathy in the cyclosporine-treated group was associated with prominent myocardial interferon-gamma gene expression, a finding absent in two thirds of the mycophenolate mofetil-treated swine. Moreover, the mycophenolate mofetil-treated swine failed to develop IgM or IgG alloantibodies. CONCLUSIONS: A short course of mycophenolate mofetil resulted in a longer allograft survival than a similar course of cyclosporine. Moreover, mycophenolate mofetil reduced the prevalence of cardiac allograft vasculopathy as compared with cyclosporine-treated controls. The salutary effect of mycophenolate mofetil may be related to its ability to decrease interferon-gamma expression in the myocardium and prevent the generation of alloantibodies.

Animals↗

PubMed2004

Transplantation-induced functional/morphological changes in rat aorta allografts differ from those in arteries of rat kidney allografts.

The functional/morphological changes observed in rat aorta allografts were compared with those seen in the arteries of rat kidney allografts. Untreated allografts (F344-to-LEW) were collected at various times post-transplantation (Tx). Vascular smooth muscle cell (SMC) constriction to phenylephrine (Phe) and endothelial cell (EC)-dependent relaxation to acetylcholine (Ach) were assessed. Neointima formation in graft vessels was assessed by histology. In aorta allografts, the effects of Phe and Ach were irreversibly abolished within 3-2 weeks post-Tx. Neointima formation was consistently detected between 4 and 8 weeks post-Tx. In kidney allografts, sign of vasculopathy was seen in 10, 30 and 40% of resistance arteries at 8, 16 and 33 weeks post-Tx, respectively. In the main renal artery, substantial neointima formation was not apparent before 33 weeks post-Tx, the vasoconstrictor effect of Phe was fully maintained until then, and Ach-induced vasorelaxation was irreversibly reduced by approximately 70% from week 2 post-Tx onwards. These results indicate that the post-Tx functional/morphological changes seen in aorta allografts do not reflect those seen in arteries of kidney allografts. Hence, renal arteries from rat kidney allografts can be considered as a more relevant model to study the cascade of events leading to Tx-induced CGA in solid organ allografts.

Acetylcholine↗

PubMed1996

Transfusion of polarized TH2-like cell populations into SCID mouse cardiac allograft recipients results in acute allograft rejection.

It has been hypothesized that TH1 cells mediate the archetypical cell-mediated immune response of acute allograft rejection, whereas TH2 cells promote allograft acceptance. To test this, we transfused SCID cardiac allograft recipients with polarized TH1-like or TH2-like graft-reactive T cells, and monitored graft function and graft-reactive immune responses in the graft recipients. Polarized THl-like cells, which were generated in vitro by stimulating syngeneic splenocytes with donor alloantigens in the presence of anti-IL-4 mAb, produced IFNg but not IL-4 when restimulated with donor alloantigen. Polarized TH2-like populations, which are generated in vitro by stimulating syngeneic splenocytes with donor alloantigens in the presence of IL-4, produced IL-4 but not IFNg when restimulated with donor alloantigen. Interestingly, bioassays of culture SN from restimulated TH1 but not TH2 cells revealed IL-2 production, although LDA analyses revealed that the TH1 and TH2 cells had identical frequencies of IL-2-producing cells. Transfusion of THl-like cells into SCID cardiac allograft recipients resulted in acute rejection within 7-10 days that was characterized by cellular infiltration, myocyte necrosis, and edema. Graft-infiltrating cells (GIC) recovered from TH1-transfused animals contained large numbers of graft-reactive IL-2-producing cells (68-269/10(6) GIC), but no LDA-detectable IL-4-producing cells. These data support the hypothesis that donor-reactive TH1 cells can promote acute allograft rejection. In contrast to the hypothesis, transfusion of the polarized TH2-like population into SCID cardiac allograft recipients also resulted in histologically similar acute rejection within 7-10 days. Infiltrating cells recovered from TH1-transfused allografts contained large numbers of graft-reactive (109-1458/10(6) GIC), LDA-detectable, IL-4-producing cells--indicating that the TH2 cells had arrived at the graft-but promoted acute allograft rejection rather than allograft acceptance.

Acute Disease↗

PubMed2001

Prolongation of allograft survival with viral IL-10 transfection in a highly histoincompatible model of rat heart allograft rejection.

BACKGROUND: The ability to express genes with potential immunoregulatory capacity could reduce the immunogenicity of allografts and result in long-term graft survival. In this study, we examine the feasibility of transferring viral interleukin-10 (vIL-10) gene into rat hearts using adenovirus by intracoronary administration. The subsequent effects of delivered vIL-10 alone or with subtherapeutic doses of cyclosporine A (CsA) on parameters of allograft rejection (AR) were also examined. METHODS: Recombinant adenovirus vectors containing vIL-10 (Ad-vIL-10) or beta-galactosidase (Ad-beta-gal) were derived from adenovirus type 5. vIL-10 expression in supernatants of transfected COS7 cell cultures and in transfected heart allografts were examined by enzyme immunoassay (EIA) and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Rat heart transplants (LEWS->ACI) were performed in five groups [group 1: no treatment, group 2: Ad-beta-gal, group 3: AdvIL-10, group 4: CsA (10 mg/kg), and group 5: Ad-vIL10+CsA (10 mg/kg)]. Allograft survival was determined by palpating heartbeats. Allograft tissues were also submitted for histological study. RESULTS: vIL-10 expression was shown in both transfected COS7 cells and heart isografts. Animals transfected with vIL-10 showed prolongation of graft survival (19.6 vs. 12 days, P<0.001) when compared to beta-gal transfected controls. Animals treated with a single low dose injection of CsA showed no significant prolongation of graft survival compared to controls (11.7 vs. 10.5 days). Animals treated with both vIL-10 and CsA demonstrated a synergistic prolongation of allograft survival compared with controls and with animals treated with CsA or vIL-10 treatment alone (36.7 days vs. 11.7, P<0.001 or 36.7 vs.19.6, P<0.001, respectively). Histological study showed that allografts from untreated controls exhibited extensive AR with loss of graft architecture by day 7 posttransplant while those from the vIL-10 group showed less AR. The best pathological scores were seen in vIL-10 + CsA-treated animals. CONCLUSIONS: 1) Delivering Ad-vIL-10 into donor hearts by intracoronary perfusion results in overexpression of vIL-10 and significantly prolongs cardiac allograft survival in a highly histoincompatible rat model. 2) Subtherapeutic doses of CsA do not prolong allograft survival, but act synergistically with vIL-10 to significantly prolong graft survival beyond that achieved with either agent alone.

Adenoviridae↗

PubMed2006

CD25+CD4+ regulatory T cells develop in mice not only during spontaneous acceptance of liver allografts but also after acute allograft rejection.

BACKGROUND: Liver grafts transplanted across a major histocompatibility barrier are accepted spontaneously and induce donor specific tolerance in some species. Here, we investigated whether liver allograft acceptance is characterized by, and depends upon, the presence of donor reactive CD25CD4 regulatory T cells. METHODS: CD25 and CD25CD4 T cells, isolated from CBA. Ca (H2) recipients of C57BL/10 (B10; H2) liver and heart allografts 10 days after transplantation, were transferred into CBA. Rag1 mice to investigate their influence on skin allograft rejection mediated by CD45RBCD4 effector T Cells. RESULTS: Fully allogeneic B10 liver allografts were spontaneously accepted by naive CBA.Ca recipient mice, whereas B10 cardiac allografts were acutely rejected (mean survival time=7 days). Strikingly, however, CD25CD4 T cells isolated from both liver and cardiac allograft recipients were able to prevent skin allograft rejection in this adoptive transfer model. Interestingly, CD25CD4 T cells isolated from liver graft recipients also showed suppressive potency upon adoptive transfer. Furthermore, depletion of CD25CD4 T cells in primary liver allograft recipients did not prevent the acceptance of a secondary donor-specific skin graft. CONCLUSIONS: Our data provide evidence that the presence of CD25CD4 regulatory T cells is not a unique feature of allograft acceptance and is more likely the result of sustained exposure to donor alloantigens in vivo.

Animals↗