Progression Of Chronic Rejection Research Articles

IL-10 Mediated Immunotolerance Augments TSG-6 Expression and Prevents Subepithelial Fibrosis in Mouse Airway Allografts

Background: Regulatory T cells (CD4+FOXP3+ Tregs) play a crucial role in the maintenance of immunotolerance to alloantigens, which is accompanied by the removal of alloreactive T effector cells (Teffs), or by polarizing Teffs-Tregs ratio in favor of Tregs to suppress alloimmune inflammation and rescue allograft from microvascular associated injuries and progression of fibrosis during transplantation. Inflammation-induced and microvascular associated airway epithelial injuries are the key pathological source of graft malfunctioning and subepithelial fibrosis, which play a major role in the progression of chronic rejection. The present study was designed to investigate the therapeutic impact of Interleukin-10 (IL-10) on immunotolerance, in particular, the reparative microenvironment, which negate airway epithelial injury, and fibrosis during graft rejection. Methods: Here, we depleted and reconstituted IL-10, and serially monitored the phase of immunotolerance, graft microvasculature, proinflammatory cytokines, airway epithelium, and subepithelial collagen in rejecting airway transplants. Results: We demonstrated that the IL-10 depletion suppresses Tregs, Tumor necrosis factor-inducible gene 6 (TSG-6) protein, graft microvasculature, and establishes a pro-inflammatory phase, which favors airway epithelial injury and subepithelial collagen deposition while the IL-10 reconstitution induces Tregs, TSG-6 expression, graft microvasculature, and establishes an immunotolerance phase, which favors airway epithelial repair and subepithelial collagen suppression. Interpretation: Collectively, these findings establish a potential reparative modulation of IL-10 associated immunotolerance on microvascular, epithelial, and fibrotic remodeling, which could provide a vital therapeutic option to rescue rejecting transplants in clinical settings. Funding Statement: This research study was financed under the RAC 2140 036 to MAK (PI) by the Office of Research Administration at the KFSH&RC, Riyadh, Saudi Arabia. Declaration of Interests: All authors declare that they have no other competing interests as defined by Journal, or other interests that might be perceived to influence the results and discussion reported in this paper. Ethics Approval Statement: All material is original and has not been reproduced from another source, and experiments using animals were approved by ACUC at the KFSH&RC.

3281 Management of Acute Rejection in Penile Allotransplantation

3281 Management of Acute Rejection in Penile Allotransplantation

Prevention of chronic renal allograft rejection by AS2553627, a novel JAK inhibitor, in a rat transplantation model

BackgroundJanus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation. MethodsLewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated. ResultsAS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial–mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts. ConclusionsThese results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

(271) - Intrapulmonary Local Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I in Association with the Progression of Chronic Rejection in Lung Allografts

(271) - Intrapulmonary Local Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I in Association with the Progression of Chronic Rejection in Lung Allografts

Allorecognition Pathways in Transplant Rejection and Tolerance

With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

Hepatic Venous Outflow Obstruction in Living Donor Liver Transplantation: Balloon Angioplasty or Stent Placement?

BackgroundThe incidence of hepatic venous outflow obstruction (HVOO) has been reported to be 5%–13% when a partial graft is used for orthotopic liver transplantation (OLT). HVOO leads to graft congestion, portal hypertension, and finally cirrhosis, which jeopardizes both graft and recipient survivals. In this study, we sought to identify perioperative factors influencing HVOO and to investigate conditions that require stent placement. Patients and MethodsFrom February 1994 to December 2010, we performed 40 living donor liver transplantations (LDLT). HVOO occurred in 5 cases (12.5%), all of which were left lobe grafts. Because HVOO was not observed in patients with body weight (BW) <30 kg, we investigated the other 28 cases with BW >30 kg. ResultsThere was no difference from unaffected subjects except for cold ischemic time (CIT), which was significantly longer: 86.2 ± 10.4 minutes vs 46.0 ± 4.8 minutes (P = .001). Balloon angioplasty, which was selected as the initial treatment for all stricture patients, improved 2 patients after 1 and 5 treatments, respectively, but 3 subjects underwent repeated HVOO, finally being treated with self-expandable metallic stents at 9, 6, and 10 years after LDLT, respectively. All patients finally resolved their strictures. ConclusionHVOO reflects intimal hyperplasia and fibrosis at the anastomotic sites or compression and twisting of the anastomosis caused by graft regeneration. In addition, progression of chronic rejection and fibrosis are possibly responsible for late-onset HVOO. Longer CIT possibly reflects difficulties in the venoplasty before anastomosis. No bleeding or thrombosis complications were observed during dilatation among our cases. The selection of the stent size for each case and careful stent deployment are important to prevent complications. Stent placement should be considered in patients with chronic rejection who are refractory to several balloon angioplasties with early-onset or late-onset HVOO.

Gastroesophageal Reflux Disease Is Associated With an Increased Rate of Acute Rejection in Lung Transplant Allografts

Purpose Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients. Methods This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded. Results The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 ( P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004). Conclusion In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation.

Gastroesophageal reflux disease after lung transplantation: Pathophysiology and implications for treatment

Gastroesophageal reflux disease (GERD) is thought to be a risk factor for the development or progression of chronic rejection after lung transplantation. However, the prevalence of GERD and its risk factors, including esophageal dysmotility, hiatal hernia and delayed gastric emptying after lung transplantation, are still unknown. In addition, the prevalence of Barrett's esophagus, a known complication of GERD, has not been determined in these patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients. Thirty-five consecutive patients underwent a combination of esophageal function testing, upper endoscopy, barium swallow, and gastric emptying scan after lung transplantation. In this patient population, the prevalence of GERD was 51% and 22% in those who had been retransplanted. Of patients with GERD,36% had ineffective esophageal motility (IEM), compared with 6% of patients without GERD (P = .037). No patient demonstrated hiatal hernia on barium swallow. The prevalence of delayed gastric emptying was 36%. The prevalence of biopsy-confirmed Barrett's esophagus was 12%. Our study shows that, after lung transplantation, more than half of patients had GERD, and that GERD was more common after retransplantation. IEM and delayed gastric emptying are frequent in patients with GERD. Hiatal hernia is rare. The prevalence of Barrett's esophagus is not negligible. We conclude that GERD is highly prevalent after lung transplantation, and that delayed gastric emptying and Barrett's esophagus should always be suspected after lung transplantation because they are common risks factors and complications of GERD.

Natural Killer Cells in Peripheral Blood and Lung Tissue Are Associated With Chronic Rejection After Lung Transplantation

Natural killer (NK) cells have the capacity to recognize and respond to alloantigen, yet their role in lung transplant rejection is not well defined. The aim of this study was to correlate NK cell numbers and immunophenotype in peripheral blood and tissue with graft function after lung transplantation. NK cell subsets were immunophenotyped in peripheral blood (n = 41). Lung tissue was stained for NK cells via CD16 and morphologic assessment (n = 30). Peripheral blood NK cells were activated in patients with chronic rejection, but the overall number of cells was lower in these patients when compared with stable patients. Furthermore, there was significantly more CD16(+) NK cells in the lung compartment of patients with bronchiolitis obliterans syndrome compared with stable patients (p = 0.001). In patients with chronic rejection, peripheral blood NK cells are activated but their numbers decrease, while the number of NK cells in the lungs increases. This suggests NK cells systemically activate and migrate to the lung during the progression of chronic rejection after lung transplantation.

Factors affecting nutritional status, response to exercise, and progression of chronic rejection in kidney transplant recipients

The nutritional status and the function of a renal graft are satisfactory in kidney transplantation patients who observe their dietary prescription. A reduction in maximal exercise test capacity in kidney transplant recipients are thought to be a consequence of uremic muscle dysfunction and also of changes in muscle structure associated with immunosuppressive therapy. Daily regular physical activity is recommended. Patients with a functioning renal transplant, as well as hemodialyzed patients, have an increased risk for development of cardiovascular diseases such as hypertension, hyperlipidemia, hyperglycemia, and obesity. The reduction of obesity and of cardiovascular risk factors in these patients are goals to be obtained by adequate nutrition, exercise, and physical activity.

A novel CD154 monoclonal antibody in acute and chronic rat vascularized cardiac allograft rejection.

The CD40-CD154 interaction is critically important in the cell-mediated immune responses. Blockade of this costimulatory pathway has been shown to prevent acute allograft rejection in murine, as well as nonhuman primate models. However, the role of the CD40-CD154 pathway in the development of chronic rejection and the effects of CD154 targeting on progression of chronic rejection have not been evaluated. We examined the effect of AH.F5, a new hamster anti-rat CD154 monoclonal antibody, in a fully allogeneic acute(u) into Lewis [LEW] (RT11) and chronic [WF.1L (RT1l) into LEW (RT1l)] vascularized cardiac allograft rejection model. In the chronic model, the antibody was evaluated for prevention (starting day of transplant) and interruption of progression (starting day 30 or 60 after transplant) of chronic vasculopathy. Graft survival, morphology, and immunohistology were evaluated. In the acute rejection model, anti-CD154 therapy alone prevented acute allograft rejection and resulted in 50% long-term allograft survival (>200 days) and donor-specific tolerance. In recipients treated with anti-CD154 monoclonal antibody in combination with a short course of cyclosporine, 100% of allografts survived long-term and all recipients achieved donor-specific tolerance. In the chronic rejection model, allografts from animals treated with the anti-CD154 antibody had a statistically significant lower score of graft arteriosclerosis and fibrosis in both the prevention and 30-day interruption groups when compared with control allografts. In addition, immunohistochemistry showed a decrease in intragraft mononuclear cell infiltration and activation. A new anti-CD154 antibody not only prevents acute allograft rejection, but also inhibits and interrupts the development of chronic rejection. In the acute rejection model cyclosporine acts synergistically with anti-CD154 therapy to prolong allograft survival and induce tolerance. In the chronic rejection model relatively early initiation of therapy is essential to prevent progression of chronic allograft vasculopathy and fibrosis.

Indirect allorecognition of donor class I and II major histocompatibility complex peptides promotes the development of transplant vasculopathy.

Recent clinical and experimental evidence suggests that indirect allorecognition may promote the development of chronic rejection, but definitive experimental studies are lacking. To study the contribution of indirect allorecognition to chronic rejection, naïve Lewis (RT1(1)) rats were immunized with synthetic Wistar Furth (WF) class II-RT1(u).D (HLA-DR-like) or -RT1(u).B (HLA-DQ-like) or class I-RT1(u).A (HLA-A-like) peptides emulsified in complete Freund's adjuvant 7 d before transplantation (n = 5 to 7/group). Experimental and control animals then acted as recipients of fully mismatched WF vascularized cardiac allografts. Recipients received immunosuppression in the form of cyclosporine at a tapering dose that allows for long-term allograft survival. Animals were sacrificed at either 3 or 6 mo, with allograft arterial luminal occlusion scored on elastin stains by a blinded observer. At 3 mo, mean vessel scores were significantly higher in the RT1(u).A-immunized versus class II-immunized and control groups (P < 0.05). By 6 mo, there was progression of chronic allograft vasculopathy and a significantly higher mean vessel score in the RT1(u).A- and RT1(u).D-immunized versus RT1(u).B and control groups (P < 0.05). In vitro studies show evidence of shifting MHC allopeptide immunogenicity. It was concluded that T cells primed by specific donor class I and II MHC allopeptides promote the development of chronic vascularized allograft rejection. These novel observations provide definitive evidence of a link between indirect allorecognition and the development and progression of chronic rejection.

Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy.

Graft loss from chronic rejection has become the major obstacle to the long-term success of whole organ transplantation. In cardiac allografts, chronic rejection is manifested as a diffuse and accelerated form of arteriosclerosis, termed cardiac allograft vasculopathy. It has been suggested that T-cell recognition of processed alloantigens (allopeptides) presented by recipient antigen-presenting cells through the indirect pathway of allorecognition plays a critical role in the development and progression of chronic rejection. However, definitive preclinical evidence to support this hypothesis is lacking. To examine the role of indirect allorecognition in a clinically relevant large animal model of cardiac allograft vasculopathy, we immunized MHC inbred miniature swine with synthetic polymorphic peptides spanning the alpha(1) domain of an allogeneic donor-derived swine leukocyte antigen class I gene. Pigs immunized with swine leukocyte antigen class I allopeptides showed in vitro proliferative responses and in vivo delayed-type hypersensitivity responses to the allogeneic peptides. Donor MHC class I disparate hearts transplanted into peptide-immunized cyclosporine-treated pigs not only rejected faster than unimmunized cyclosporine-treated controls (mean survival time = 5.5 +/-1.7 vs. 54.7 +/-3.8 days, P < 0.001), but they also developed obstructive fibroproliferative coronary artery lesions much earlier than unimmunized controls (<9 vs. >30 days). These results definitively link indirect allorecognition and cardiac allograft vasculopathy.

Rapamycin in transplantation: A review of the evidence

Rapamycin in transplantation: A review of the evidence. The calcineurin inhibitors have been the mainstays of immunosuppression for solid organ transplantation over the last two decades, but nephrotoxicity limits their therapeutic benefit. Rapamycin is a new drug with both immunosuppressant and antiproliferative properties that has a unique mechanism of action distinct from that of the calcineurin inhibitors. It has a role as a maintenance immunosuppressant either alone or in combination with a calcineurin inhibitor and can also be used to treat refractory acute rejection. Theoretical evidence suggests that it may limit the development and progression of chronic rejection in transplant recipients, but this has yet to be confirmed. This review examines the current in vitro animal and human work underlying the use of rapamycin and, in addition, comments on the pharmacokinetics and side-effect profile of this promising new agent.

Effects of cytomegalovirus infection and prolonged cold ischemia on chronic rejection of rat renal allografts.

Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way. The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.

Effects of cytomegalovirus infection and prolonged cold ischemia on chronic rejection of rat renal allografts

Abstract Previous studies have demonstrated that both cytomegalovirus (CMV) infection and prolonged cold ischemia of the allograft (CI) are associated with chronic rejection of renal transplants. The purpose of this study is to investigate the effect of CMV infection, of CI and of the combination of both, on the progression of chronic rejection, and to obtain a more detailed insight in their effects on the expression of adhesion molecules. Therefore, a rat transplantation model was used. Lewis recipients of renal allografts (with and without CI) from MHC-incompatible Brown Norway rats were inoculated with rat CMV or left uninfected. CMV infection alone resulted in an increased influx of CD4+ cells and macrophages early after infection, and in an increase in glomerular sclerosis and intima proliferation. CI caused an increase in infiltrating NK cells and an effect on intimal proliferation, glomerular sclerosis, and tubular atrophy. When CMV infection and CI were combined, an additive effect could be measured. This was however not the case for the function of the kidney. The creatinin showed a synergistic effect of the two influencing factors. Due to the CMV infection, an increase in CD49d cells was detected. CI resulted in an increase in CD18 cells and an increase in the expression of CD62P on vessels, and CD54 and CD44 on tubules. When CMV infection and CI were combined, all the effects caused by CMV and CI alone were present in an additional way. The results of the present study suggest that special attention should be paid to the recipient of an ischemically injured graft when either the donor or the recipient is CMV-infected. The patterns seen in histology, the infiltration of leukocytes and the expression of adhesion molecules, suggest that CI and CMV infection both have an effect on rejection, but act by different mechanisms.

Does transforming growth factor beta 1 play a role in the pathogenesis of chronic allograft rejection?

To investigate the potential role of Transforming Growth Factor beta 1 (TGF beta 1) in the pathogenesis of chronic allograft rejection, we studied TGF beta 1 expression in a rat aortic allograft model. mRNA and protein expression of total and endogenously active TGF beta 1 were analysed in infra-renal orthotopic aortic syngeneic and allogeneic grafts and matched with the histological appearances of the grafts, 2, 4 and 12 weeks post-transplantation. Serum levels of TGF beta 1 were also measured. The level of TGF beta 1 m RNA and protein expression appeared highest 2 and 4 weeks following transplantation in both syngeneic and allogeneic grafts, with significantly elevated levels of mRNA expression in the 2 week allograft specimens. These time-points correlate histologically with maximal inflammatory cell infiltration of the grafts. By 12 weeks post-transplantation, TGF beta 1 mRNA expression is reduced in allogeneic grafts compared to syngeneic grafts. However, detectable levels of total and endogenously active TGF beta 1 protein levels in the allografts exceed those measured in the syngeneic grafts at this time point. These results demonstrate the complex expression pattern of this growth factor during the progression of chronic rejection and suggest an aetiological link between TGF beta 1 and the process of accelerated graft atherosclerosis.

Carvedilol treatment of kidney graft recipients with chronic rejection

Carvedilol is an antihypertensive drug with properties that may be potentially beneficial for kidney graft recipients. The purpose of the study was to investigate if progression of an established chronic rejection may be attenuated or reversed by carvedilol. An open, single-centre, phase II, pilot study, with a 2-yr follow-up, was performed in 25 kidney graft recipients with chronic rejection or accelerated transplant atherosclerosis. Seventeen patients had stable graft function assessed by serum creatinine levels. Eight patients withdrew from the study due to lack of efficacy (increase in serum creatinine 174-477 micromol/L (46-191%) from the initial levels). However. these patients had higher serum creatinine levels and proteinuria already at the start of the study. Both systolic and diastolic blood pressure, as well as heart rate, were stable in all study patients. Low density lipoprotein (LDL)/high density lipoprotein (HDL) cholesterol ratio decreased from 4.7 +/- 1.9 at 1 month to 3.5 +/- 1.2 at 18 months (p < 0.05), and MDA plasma levels decreased from 0.714 +/- 0.119 to 0.493 +/- 0.073 micromol/L after 3 months of carvedilol treatment (p < 0.05). No attenuation of progression of chronic graft rejection by carvedilol treatment was observed in the study. It is suggested that the process of chronic rejection could not be reversed by carvedilol because the patients included in the study already had severe morphological and functional changes of the graft. In conclusion, our study demonstrated that carvedilol provides a good control of blood pressure in renal transplanted patients. Carvedilol treatment had a beneficial effect on lipid pattern and reduced lipid oxidation, but there was no obvious effect on progression of chronic rejection.

The relative influence of antigen-dependent and independent factors for development and progression of chronic rejection

The relative influence of antigen-dependent and independent factors for development and progression of chronic rejection

Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection.

Early blockade of T cell-costimulatory activation pathways prevents development of experimental chronic allograft rejection. Ongoing T cell recognition of alloantigen and activation may also play an important role in progression of chronic rejection, but definitive evidence is lacking. We used the fusion protein CTLA4Ig to block CD28-B7 T cell costimulation late after the onset of initial graft injury. Using the F334 into LEW rat model of chronic renal allograft rejection, transplant recipients were treated with a 10-d course of cyclosporine, and a subgroup received a single injection of CTLA4Ig at 8 wk after transplant. Functionally, CTLA4Ig administration prevented development of progressive proteinuria (14.3+/-4.1 mg/24 h versus 41.0+/-12.0 mg/24 h at 24 wk after transplant, P < 0.05). Histologically, graft mononuclear cell infiltration, glomerular hypertrophy, focal and segmental glomerulosclerosis, and intimal vascular hyperplasia were all attenuated in CTLA4Ig-treated animals. Lastly, reverse transcriptase-PCR and immunohistologic studies showed a significant reduction in the intragraft expression of key products of T cell and macrophage activation, and upregulation of what have recently been termed as "protective" genes, including the bcl family members, Bcl-2 and Bcl-xL, and hemoxygenase. Our data are the first to demonstrate that blocking T cell-costimulatory activation late after transplantation, after initial graft injury, prevents progression of chronic allograft rejection supporting the hypothesis that ongoing T cell recognition of alloantigen and activation are key mediators of ongoing chronic allograft rejection.