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PubMed1982

Structure and function of small bowel allografts in the dog: immunosuppression with cyclosporin A.

Pairs of mongrel dogs received orthotopic total small bowel allografts. Half were treated with the immunosuppressive agent cyclosporin A and the other half were not. Ten untreated dogs survived a mean of 12.5 days (range from 7 to 25 days). They lost up to 30% of their initial body weight and rejection with hemorrhagic necrosis was usually the cause of graft failure. The mean survival of 11 dogs treated with cyclosporin A was 90.6 days (range 9 to 286 days) with early deaths being due to pneumonia or volvulus. Intestinal mucosa appeared normal, but there was some smooth muscle hypertrophy. Reconnection of lymph vessels was complete in all dogs examined more than 21 days after allografting. Two dogs survived for 203 and 221 days, respectively, and one dog remains alive and well 287 days after operation. The long-term survivors remained healthy, with steady body weights, formed stools, normal plasma protein values and xylose absorption curves that did not differ from those of autografted dogs. Roentgenography after a barium meal and follow-through study showed normal mucosa. The transit time was around 60 minutes (normal 150 minutes). Late, acute episodes of rejection occurred in two dogs, when blood levels of cyclosporin A were low (less than 400 ng/ml). Bowel mucosa showed ulceration and villous atrophy, with lymphoid infiltration, leading to malabsorption as a terminal event. Cyclosporin A is effective in increasing the duration of survival in dogs with small bowel allografts while maintaining essentially normal bowel structure and good function.

Animals↗

PubMed1995

Peripheral nerve allograft transplantation with FK506: functional, histological, and immunological results before and after discontinuation of immunosuppression.

Two-centimeter nerve allografts were transplanted across a major histocompatibility barrier from donor ACI rats into a 0.5-cm gap in the sciatic nerve of recipient Lewis rats and immunosuppressed with FK506, 2 mg/kg per day for 3 months. One group of animals continued to receive intermittent immunosuppression with FK506, 2 mg/kg twice a week for another 2 months, whereas the second group of animals received no further immunosuppression in order to determine whether rejection of nerve allografts can still occur after immunosuppression is withdrawn, even after the axons have regenerated through the nerve graft. The sciatic function index improved from -76.3 at 3 months to -46.6 at 5 months in those animals continuing to receive intermittent immunosuppression, but only improved to -66.8 at 5 months when immunosuppression was discontinued. Similarly, somatosensory evoked potentials demonstrated an improvement in relative latency from 2.3 msec at 3 months to 0.34 msec at 5 months in animals continuing to receive intermittent immunosuppression, but only improved to 1.29 msec at 5 months when immunosuppression was discontinued. Nerve allografts continuing to receive intermittent immunosuppression showed no signs of rejection by light or electron microscopy and no significant difference compared with isografts, whereas nerve allografts whose immunosuppression had been stopped at 3 months showed mild signs of rejection, less regeneration, and a smaller number of nerve fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Effect of liposomal methylprednisolone on heart allograft survival and immune function in rats.

Liposomal methylprednisolone (L-MPL) applied in monotherapy prolonged cardiac allograft survival in rats in comparison with the same dosage regimen of drug in solution (Solu-Medrol). The most efficacious treatment consisted of a 2-mg/kg i.v. dose of L-MPL twice a week (group III), producing survival up to 30 days, followed by a 4-mg/kg/week dose of L-MPL (group IV) and a single 2-mg/kg dose of L-MPL (group II). Survival in animals receiving Solu-Medrol as a 2-mg/kg dose twice a week (group V) did not differ from untreated animals. Only daily 4-mg/kg doses of methylprednisolone (MPL) in solution (group VI) were as effective as group III. The concentrations of MPL in liver and spleen were detectable for 26 days after the last dose of L-MPL, showing tissue selective sequestration of drug. Treatment at these low doses did not suppress endogenous corticosterone determined 24 hr or later in plasma. The administration of steroid caused significant immunosuppression in most animals as measured by inhibition of splenocyte blastogenesis induced with phytohemagglutinin. Cellular immunity data did not differ significantly between groups, but alterations occurred at day 14 to 15 after surgery: CD3, CD4 and ratio CD4:CD8 subsets of cells showed minimum values; CD8, CD4CD8, CD25 and white blood cell counts were at maximum at this time. Slight but significant differences between Immunoglobulin M suppression in group II compared to group I or V were found, whereas Immunoglobulin G values were unchanged. The transplantation and treatment with steroid decreased the total body weight of animals but increased weights of internal organs, particularly spleen, similarly for all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1997

Nephron sparing surgery for de novo renal cell carcinoma in an allograft kidney: a case report.

De novo renal cell carcinoma in a renal allograft is rare and has special implications in renal transplant recipients. We describe a patient with a renal allograft who developed a de novo renal cell carcinoma in the functioning renal allograft 258 months after transplantation. The patient underwent enucleation of the tumor because preoperative MRI showed it was well-encapsulated. A DNA banding study showed that the tumor originated from the donor. Indications for conservative renal surgery in renal cell carcinoma have been increasing. Accordingly, 1 option in the treatment of de novo renal cell carcinoma in a functioning renal allograft is enucleation as a method of nephron sparing surgery.

Autoradiography↗

PubMed1980

Assessment of T cell function with a skin allograft assay.

The adoptive transfer of cytotoxic effector cells to induce accelerated skin allograft rejection in the normal murine host was used as an assay of lymphocyte function in vivo. Splenocytes sensitized in vivo caused specific accelerated skin allograft rejection when administered i.v. at a dose of 5 X 10(7) cells 1 day after grafting. Graft rejection was specific for the immunizing alloantigen and could not be transferred with freeze-thawed or irradiated cytotoxic cells. In this assay the i.v. and local routes of administering cytotoxic cells were effective whereas the i.p. and s.c. routes were not. T cells were necessary in that pretreatment of the cells with anti-Thy-1.2 plus rabbit complement abrogated this phenomenon. Immune cells from spleens of mice sensitized but no longer actively cytotoxic did not demonstrate in vivo activity. If hyperimmunized mice were challenged by i/p. allogeneic tumor, their spleen cells were highly cytotoxic by in vitro assay but acted as suppressor cells in vivo by prolonging skin graft survival. Adoptively transferred in vivo sensitized cells subsequently expanded in number by T cell growth factor did not demonstrate in vivo activity. This skin allograft assay may be used to demonstrate T cell activity in vivo by inducing accelerated allograft rejection, and immune suppression by prolonging graft survival. Also a comparison of in vivo and in vitro effects was possible.

Animals↗

PubMed1993

Improved renal function in mouse kidney allografts lacking MHC class I antigens.

The immunological responses that lead to rejection of organ and tissue transplants are triggered by the recognition of proteins encoded within the MHC. The relative contributions of responses directed toward MHC class I compared with class II in the loss of functional integrity of vascularized organ grafts have been difficult to define. The recent development of technologies which allow the generation of mice in which specific genes have been altered by gene targeting offers a new approach to addressing this question. We examine here the rejection of kidney allografts from mice lacking native MHC class I Ag. These mice were obtained from embryonic stem cells in which the beta 2 microglobulin (beta 2m) gene had been disrupted by homologous recombination. We found a significant improvement in function of renal allografts from MHC class I-deficient donors compared with allografts from donors with normal MHC class I expression. Surprisingly, the improved function of the MHC class I-deficient grafts was not associated with differences in mononuclear inflammatory cell infiltration of these grafts nor in differences in alloreactive proliferative or cytotoxic T cell responses. However, we did find differences in alloantibody response between the groups. Recipients of control allografts produced antibodies against both donor MHC class I and II, whereas recipients of MHC class I-deficient grafts formed alloantibodies primarily against donor MHC class II Ag. These studies confirm that immune responses directed toward donor MHC class I alloantigens contribute to kidney transplant dysfunction in this model. Also, these findings suggest that, at least for renal transplants, genetic manipulations which reduce MHC class I expression may be effective in overcoming some of the effects of MHC incompatibility.

Animals↗

PubMed2006

Conversion from calcineurin inhibitor to sirolimus for renal function deterioration in kidney allograft recipients.

BACKGROUND: Calcineurin inhibitors play an important role in chronic allograft dysfunction. Sirolimus is an interesting alternative in renal transplant patients because it is less nephrotoxic than calcineurin inhibitors. METHODS: A chart review of the clinical outcome of kidney transplant patients converted to sirolimus with progressive allograft dysfunction is reported herein. Fifteen patients (average age: 32.3 years, 44 months mean time of conversion) were included. Indication for conversion was a >20% increase in serum creatinine over the last 6 months or progression to the range of 2-4.5 mg/dL. Patients underwent abrupt cessation of cyclosporine and sirolimus addition at 2-5 mg/day. RESULTS: Concomitant immunosuppression remained unchanged during conversion. Targeted sirolimus level was 8-12 ng/mL. Serum creatinine dropped from pre-conversion level of 2.75 +/- 0.83 to 2.14 +/- 0.67 and 1.97 +/- 0.66 mg/dL at 3 and 6 months (p <0.05). There was a significant decrease in blood urea nitrogen, hemoglobin and serum calcium at 3 months post-conversion as well as serum calcium and potassium at 6 months post-conversion (p <0.05). There were no rejection episodes. Patient and graft survival was 100% with three infectious complications. CONCLUSIONS: Monitored sirolimus conversion with sharp withdrawal of calcineurin inhibitor is an alternative for patients with deteriorating renal function and chronic allograft nephropathy.

Adult↗

PubMed1983

Donor-specific decreased cell-mediated cytotoxicity in recipients of well functioning, one HLA haplotype-mismatched kidney allografts.

Patients with well functioning kidney grafts from one HLA haplotype-mismatched related donors were studied 2 to 10 years after transplantation. No direct cell-mediated lympholysis (CML) toward donor cells was found. After in vitro sensitization in mixed lymphocyte culture, the recipient effector cells were not able to significantly kill donor target cells at an effector to target cell ratio of 50:1, while the HLA-A,B,D/DR-identical sibling of the recipient could generate strong cytotoxicity toward the donor at similar effector to target cell ratios. Nevertheless, the patient developed strong cytotoxicity toward third-party targets. Our findings indicate in vivo depletion of cytotoxic cells with specificity for donor antigens. No correlation between the mixed lymphocyte culture (MLC) response and the ability to generate cytotoxic cells could be found in recipient-donor combinations. In looking for in vivo generated suppressor cells toward the donor, a moderate suppression was found in three of six patients studied.

Cytotoxicity, Immunologic↗

PubMed1997

Inflammatory cell-derived NO modulates cardiac allograft contractile and electrophysiological function.

We previously demonstrated that inhibition of inducible nitric oxide (NO) synthase (iNOS) ameliorated acute cardiac allograft rejection. This study used a rat cardiac transplant model to characterize contractile and electrophysiological dysfunction during early acute rejection, further examine the role of NO and iNOS in this process, and determine which cells expressed iNOS during early rejection. During early acute rejection, before significant myocyte necrosis, allograft papillary muscles had reduced tension development and rates of tension development and decline during beta-adrenergic, adenylate cyclase, and calcium stimulation compared with isograft and normals [e.g., tension of 36 (allograft) vs. 73 (isograft) mN/mm2 during calcium stimulation, P < 0.001]. Allografts had resting membrane potential depolarization and reduced action potential amplitude and upstroke velocity. iNOS mRNA was expressed in infiltrating inflammatory cells but not in allograft myocytes, endothelial cells, or isografts. Corticosteroids attenuated allograft contractile and electrophysiological dysfunction and inhibited iNOS enzyme activity. Direct iNOS inhibition with aminoguanidine inhibited NO production and prevented allograft contractile and electrophysiological dysfunction (e.g., tension of 64 mN/mm2 during calcium stimulation, P < 0.001). We conclude that 1) early allograft rejection caused contractile and electrophysiological dysfunction that was largely mediated by iNOS expression in infiltrating inflammatory cells, 2) corticosteroid-mediated amelioration of allograft contractile and electrophysiological dysfunction may reflect inhibition of iNOS, and 3) iNOS inhibition may offer an alternative in management of immune-mediated myocardial dysfunction.

Action Potentials↗

PubMed1991

Pancreas function index: an early monitor of allograft rejection.

The lack of reliable markers for the early diagnosis of allograft rejection is a major obstacle preventing improved results in clinical pancreas transplantation. Using a vascularized whole-pancreas transplant model in the rat, with exocrine ductal drainage into the lower urinary tract, we explored the possibility that a change in an index of pancreatic function (IPF), viz., urine volume, urine pH, and urine amylase (UA) in composite, may provide an earlier and more specific indicator of rejection than a decline in UA levels alone. Six Lewis-to-Lewis rat isograft and 12 ACI-to-Lewis allograft recipients were studied. Ten nontransplanted diabetic Lewis rats served as a control group. Euglycemia was restored in all the recipients of isografts, and was maintained for over a year. In the allograft group, rejection occurred on Days 7-9, with a mean graft survival time of 8.1 +/- 0.1 days. Peak UA levels and IPF during normal allograft function were 2422 +/- 353 U/ml and 100 +/- 14, respectively, whereas levels heralding rejection were 600 U/ml and 25 (P less than 0.05). The diagnosis of rejection based on the IPF resulted in significantly greater specificity and an earlier prediction time compared with UA alone (2.4 +/- 0.3 vs 1.6 +/- 0.2 days); the IPF permitted the successful prediction of rejection 3 or more days prior to hyperglycemia in 6 of 12 (50%) grafts, whereas only 1 of 12 (8%) rejection episodes was successfully predicted when the rejection criterion was based on UA. In conclusion, early diagnosis of rejection was achieved by a composite index of pancreatic function, improving the ability to predict pancreas-allograft rejection 24 to 48 hr prior to a fall in UA levels.

Amylases↗

PubMed1996

Function of cryopreserved arterial allografts under immunosuppressive protection with cyclosporine A.

PURPOSE: Cryopreserved arterial allografts may be used for arterial reconstructive procedures. In this experimental study cryopreserved arteries were used as autografts and as allografts with or without immunosuppression with cyclosporine A. METHODS: In group A (three dogs, six bilateral grafts) cryopreserved carotid artery autografts were implanted. In groups B and C female mongrel dogs (three dogs and six bilateral grafts in each group) received cryopreserved male carotid artery allografts. Dogs in group C were treated with cyclosporine A (25 mg/kg/day). After 3 months of implantation patency was assessed by angiography. Contractile responses to KCl and phenylephrine (Phe) and the endothelium-dependent relaxation response to methacholine (Met) were examined in segments of the grafts after excision. Medial thickness was assessed semiquantitatively. The grafts were stained for sex chromatin analysis to determine the origin of cells in allografts. RESULTS: Patency: group A, 100% (6 of 6), group B, 66.6% (4 of 6), and group C, 100% (6 of 6). Functional responses: before implantation, after thawing, 2.7 +/- 0.5 mN (KCl), 4.8 +/- 1.0 mN (Phe), and 0.0% +/- 0.0% (Met), group A, 36.9 +/- 10.6 mN (KCl), 31.5 +/- 14.4 mN (Phe), and 59.3% +/- 20.4% (Met), group B, 0 for all agents used, group C, 34.0 +/- 7.5 mN (KCl), 28.8 +/- 7.0 mN (Phe), and 46.2% +/- 3.2% (Met). Morphologic characteristics: the media of grafts in group B showed significant thinning (p < 0.05). Smooth-muscle cells in vessel walls of grafts in group C were of female origin. CONCLUSION: Arteries showed no function and loss of endothelial integrity after cryopreservation and thawing. After 3 months of implantation cryopreserved arterial autografts and allografts under immunosuppressive treatment with cyclosporine A showed 100% patency and return of functional responses resulting from repopulation of grafts by host cells.

Animals↗

PubMed1999

Long-term survival and function of intrahepatic islet allografts in baboons treated with humanized anti-CD154.

Clinical islet cell transplantation has resulted in insulin independence in a limited number of cases. Rejection, recurrence of autoimmunity, and impairment of normal islet function by conventional immunosuppressive drugs, e.g., steroids, tacrolimus, and cyclosporin A, may all contribute to islet allograft loss. Furthermore, intraportal infusion of allogeneic islets results in the activation of intrahepatic macrophages and endothelial cells, followed by production of proinflammatory mediators that can contribute to islet primary nonfunction. We reasoned that the beneficial effects of anti-CD154 treatment on autoimmunity, alloreactivity, and proinflammatory events mediated by macrophages and endothelial cells made it an ideal agent for the prevention of islet allograft failure. In this study, a nonhuman primate model (Papio hamadryas) was used to assess the effect of humanized anti-CD154 (hu5c8) on allogeneic islet engraftment and function. Nonimmunosuppressed and tacrolimus-treated recipients were insulin independent posttransplant, but rejected their islet allografts in 8 days. Engraftment and insulin independence were achieved in seven of seven baboon recipients of anti-CD154 induction therapy administered on days -1, 3, and 10 relative to the islet transplant. Three of three baboons treated with 20 mg/kg anti-CD154 induction therapy experienced delayed rejection episodes, first detected by elevations in postprandial blood glucose levels, on postoperative day (POD) 31 for one and on POD 58 for the other two. Re-treatment with three doses of anti-CD154 resulted in reversal of rejection in all three animals and in a return to normoglycemia and insulin independence in two of three baboons. It was possible to reverse multiple episodes of rejection with this approach. A loss of functional islet mass, as detected by reduced first-phase insulin release in response to intravenous glucose tolerance testing, was observed after each episode of rejection. One of two baboons treated with 10 mg/kg induction therapy became insulin independent post-transplant but rejected the islet graft on POD 10; the other animal experienced a reversible rejection episode on POD 58 and remained insulin independent and normoglycemic until POD 264. Two additional baboon recipients of allogeneic islets and donor bone marrow (infused on PODs 5 and 11) were treated with induction therapy (PODs -1, 3, 10), followed by initiation of monthly maintenance therapy (for a period of 6 months) on POD 28. Rejection-free graft survival and insulin independence was maintained for 114 and 238 days, with preservation of functional islet mass observed in the absence of rejection. Prevention and reversal of rejection, in the absence of the deleterious effects associated with the use of conventional immunosuppressive drugs, make anti-CD154 a unique agent for further study in islet cell transplantation.

Animals↗

PubMed1990

Long-term, low-dose cyclosporine treatment of renal allograft recipients. A randomized trial.

Ninety-two adult renal allograft recipients, receiving baseline immunosuppression with CsA and prednisone, were assigned randomly to one of the following regimens. CsA was discontinued (D/C group) in 47 recipients who were then maintained on Aza and prednisone; or Aza was added to continued low-dose CsA and prednisone (triple drug [TD] group) in 45 patients. Entry into the study required an absence of rejection and a stable creatinine for at least four months prior to randomization. The mean month of randomization was 8.34 +/- 2.9 for the D/C group, and 7.2 +/- 3.2 for the TD group. Following randomization, a significantly greater rate of rejection (P less than .01) was observed in the D/C group (40%) than in the TD group (13%). With a mean follow-up of 30 months, 41/47 of D/C allografts (87.2%) and 39/45 TD allografts (86.6%) were functioning. Nevertheless, rejection had a persistent adverse effect on allograft function, in both the D/C and TD groups, up to 36 months following randomization. Parameters such as donor-type and rejection prior to randomization did not identify recipients at risk for rejection following randomization. Therefore, although the CsA withdrawal regimen might be ideal, the opportunity to select appropriate candidates remained elusive. In contrast, the safety of the TD regimen became apparent. Neither significant nephrotoxicity nor hypertension was observed, and the opportunity for less daily prednisone was evident. Despite its additional cost, the TD regimen utilizing indefinite low-dose CsA, is preferred.

Adult↗

PubMed1998

Impairment of peroxisomal structure and function in rat liver allograft rejection: prevention by cyclosporine.

BACKGROUND: During allograft rejection, cytokines and lipid mediators contribute to cell injury and organ failure. Peroxisomes play a crucial role in lipid metabolism, including the degradation of lipid mediators by peroxisomal beta-oxidation. Therefore, we investigated the alterations of hepatic peroxisomes after allogeneic rat liver transplantation. METHODS: MHC-incompatible Dark Agouti (RT1a) donor rats and Lewis (RT1(1)) recipient rats were used for allogeneic transplantation. For immunosuppression, a group of these animals received cyclosporine (CsA) intraperitoneally (1 mg/kg body weight per day). Lewis rats were used for isogeneic transplant combination. Ten days after transplantation, livers were investigated using morphometrical methods for determination of peroxisomal diameter and volume density. The activities of peroxisomal catalase (CAT) and acyl-coenzyme A oxidase (AOX) were determined, and the corresponding proteins were evaluated by quantitative immunocytochemistry and immunoblotting. The expressions of mRNAs encoding CAT and AOX were investigated by Northern blotting. RESULTS: The volume density and diameter of peroxisomes were significantly decreased in allogeneic transplanted livers but were unchanged in CsA-treated animals. Both the activities of CAT and AOX and their protein levels were significantly reduced in liver allografts. Moreover, the corresponding mRNA levels of CAT and AOX were decreased significantly in liver allografts, whereas CsA treatment led to an increase of those mRNAs. Isogeneic transplanted livers showed only a slight reduction of the corresponding enzyme values. CONCLUSIONS: Peroxisomes are severely affected both morphologically and functionally after allogeneic liver transplantation. These results suggest that impairment of peroxisomal lipid beta-oxidation could contribute to the pathogenesis of the rejection process by decreased catabolism of lipid mediators involved in the regulation of the inflammatory response. CsA, in addition to its immunosuppressive effects, may contribute to allograft survival by maintenance of those important peroxisomal functions.

Acyl-CoA Oxidase↗

PubMed2002

Short-term outcomes of Thymoglobulin induction in pediatric renal transplant recipients.

No data are currently available that describe the clinical outcomes associated with Thymoglobulin (rabbit polyclonal anti-thymocyte globulin) induction in pediatric renal transplant recipients. We report the outcomes of 17 pediatric renal transplant recipients (mean age 10.1+/-5.2 years) transplanted between 1 August 1999 and 31 July 2001. Eleven patients (65%) were Caucasian and 6 (35%) were African-American. Eleven (65%) recipients received cadaveric allografts. Two patients (12%) were second allograft recipients. One patient had primary allograft non-function secondary to vascular thrombosis. Two patients (12%) had delayed allograft function. Immunosuppression consisted of Thymoglobulin induction (mean number of doses 6+/-1.7) with tacrolimus (62%) or cyclosporine A (38%), mycophenolate mofetil, and prednisone. One year post transplant, patient and graft survival was 100% and 93%, respectively. No acute rejection episodes occurred during the first 6 months after transplantation in any of the recipients. Additionally, no rejection episode occurred among the 14 patients followed for 1 year after transplant. The incidences of asymptomatic cytomegalovirus (CMV) and Epstein-Barr virus (EBV) seroconversion at 1 year in seronegative recipients with a seropositive donor were 100% of 4 patients and 0% of 4 patients, respectively. No symptomatic CMV or EBV infections and no post-transplant lymphoproliferative disease have occurred in any patient. These short-term data suggest that Thymogobulin induction is safe and effective in combination with triple immunosuppressive therapy for preventing early rejection in pediatric renal transplant recipients.

Acute Disease↗

PubMed2006

Rescue therapy with tacrolimus and mycophenolate mofetil does not prevent deterioration of graft function in C4d-positive chronic allograft nephropathy.

BACKGROUND: Humoral alloresponses may contribute to chronic allograft nephropathy (CAN) in a subset of kidney transplant recipients. For chronic humoral rejection, the efficacy of rescue therapy with tacrolimus and mycophenolate mofetil has been suggested. METHODS: Eleven recipients with C4d-positive CAN (index biopsy performed after a median of 3 years posttransplantation), who had been on cyclosporine A-based immunosuppression, were converted to tacrolimus, and if not part of basal therapy, to mycophenolate mofetil. We evaluated the effect of this tacrolimus/mycophenolate mofetil rescue therapy on clinical outcomes and on alloantibody formation detected with flow cytometric testing of panel-reactive antibody. RESULTS: Tacrolimus/mycophenolate mofetil rescue therapy (plus anti-rejection treatment in six recipients with additional signs of acute cellular rejection) failed to prevent progressive deterioration of graft function. Four patients returned to dialysis after 4 to 18 months. Serial post-transplant serology detected HLA class I and/or II reactivity in seven recipients. Tacrolimus/mycophenolate mofetil therapy did not affect the time course of alloantibody levels. One patient with C4d-positive transplant glomerulopathy, who did not respond to tacrolimus/mycophenolate mofetil rescue therapy, developed nephrotic-range proteinuria associated with a rapid decline of allograft function. Despite considerable reduction in alloantibody levels and nearly complete clearance of C4d deposits, immunoadsorption failed to prevent graft failure in this patient. CONCLUSION: Our data argue against the efficacy of tacrolimus/mycophenolate mofetil rescue therapy in established C4d-positive chronic allograft dysfunction. Prospective trials are needed to evaluate whether early initiation of this or other antihumoral strategies are capable of effectively preventing alloantibody-mediated chronic graft injury.

Adult↗

PubMed1992

Renal allograft rejection: induction and function of adhesion molecules on cultured epithelial cells.

The interaction of graft-infiltrating immune cells with donor parenchymal cells is an important early event in allograft rejection. This binding is stabilized by interaction of antigen-independent 'adhesion' molecules expressed on the two cell types. As the level of expression of these molecules can be altered during inflammation, a series of experiments was performed to examine the effects of the inflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) on adhesion molecules expressed by cultured human renal tubular epithelial cells. These cells constitutively expressed ICAM-1 and LFA-3. Incubation with IFN-gamma increased expression of ICAM-1 but had no significant effect on expression of LFA-3 (P greater than 0.05). Incubation with TNF-alpha increased expression of both ICAM-1 and LFA-3; IFN-gamma synergized with TNF-alpha to further augment expression of these molecules. Peripheral blood lymphocytes (PBL) showed an enhanced binding to allogeneic renal epithelial cell monolayers which had been pretreated with IFN-gamma or TNF-alpha. MoAbs specific for ICAM-1 or its ligand LFA-1 inhibited adhesion of PBL to either IFN-gamma- or TNF-alpha-pretreated renal cells. By contrast, antibodies specific for LFA-3 or its ligand CD2 only significantly blocked PBL adhesion to renal cells which had been pretreated with TNF-alpha. Combination of antibodies specific for multiple components of the adhesion systems produced greater inhibition of adhesion than was produced by any single MoAb. These results suggest that the inflammatory cytokines IFN-gamma and TNF-alpha up-regulate expression of functional ICAM-1 and LFA-3 molecules which can augment the binding of potentially graft-damaging lymphoid cells to renal tubular epithelial cells.

Antigens, CD↗

PubMed2004

Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation.

OBJECTIVE: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used serial studies to evaluate changes in coronary endothelial function in patients with and without clinically evident CAV. BACKGROUND: In serial studies with intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. METHODS: We studied 45 patients annually, beginning at transplantation until pre-specified end-points (angiographic CAV or cardiac death) were reached. At each study, we measured coronary endothelial function using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and Doppler velocities. RESULTS: Of the 45 patients studied, 9 reached end-points during the study (6 had CAV and 3 died). The mean annual change in area response to acetylcholine was -4.5% +/- 3.0% in patients who reached end-points and -0.9% +/- 1.5% in those who did not (p = 0.04). The mean annual decrement in flow response to acetylcholine was greater in patients who reached end-points (-31% +/- 11% vs -5% +/- 5%, p = 0.08). Responses to adenosine and nitroglycerin did not differ. CONCLUSIONS: When serial responses were evaluated, patients with end-points had more rapid decreases in endothelial function. The rate of disease progression may be more important than the absolute degree of intimal thickening in early CAV. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function may provide important prognostic information about the development of CAV after heart transplantation.

Blood Flow Velocity↗