Chronic Allograft Vasculopathy Research Articles

Mitochondrial Activity - a Novel Strategy for Prevention and Reversion of Transplant Vasculopathy

Background: This study aimed at investigating the efficacy of dichloracetate (DCA) to prevent the development and progression of chronic allograft vasculopathy (CAV) by regulating the mitochondrial metabolism of aberrant proliferating smooth muscle cells. Methods: Orthotopic aortic transplantations were performed in the PVG-to-ACI rat model and followed over 120 days. Immunosuppression with DCA (0.75mg/L) or everolimus+clopidogrel (4 mg/kg and 1mg/kg per os, respectively) was either started early or delayed when CAV was already present. Through levels were monitored. Aortic luminal obliteration was quantified using computer morphometry and confocal microscopy. Donor-reactive antibodies were quantified by flow cytometry. Results: Untreated animals developed CAV with luminal obliteration of 40.1±24.2% after 120 days. Continuous immunosuppression with DCA or everolimus/clopidogrel effectively prevented the development of vasculopathy (7.9±4 and 8.1±12.9, respectively; p< 0.001 vs. no treatment). When the start of the immunosuppressive regimen was delayed until postoperative day 80, DCA and everolimus/clopidogrel inhibited a progression of established CAV (6.6±8 and 5.3±4.6; p< 0.001 vs. no treatment). Even more importantly, both treatment regimens did also reverse the luminal obliteration (p< 0.001). Interestingly, delayed treatment of DCA induced apoptosis resulting in shrinking hyperplasia area and inhibition of aberrant SMC proliferation. A stable elevation of donor-reactive IgG-antibody levels was found over 120 days in the absence of treatment. DCA was very well tolerated. Conclusions: DCA prevents the development of CAV and not only inhibits a progression of established disease, but also reverses the established disease by inducing apoptosis. It shows a similar efficacy but a safer drug profile when compared to everolimus/clopidogrel, since only aberrant SMC are affected.

Human Amniotic Fluid Stem Cells Reduce Neointimal Formation and Inflammation in a Model of Aortic Allograft Vasculopathy

Introduction: Chronic allograft vasculopathy (CAV) is a major limiting factor of long-term allograft survival. Although some mechanisms involved in CAV have already been identified, there is no specific treatment for this clinical condition. Considering the immune-inflammatory events involved in the development of CAV, therapeutic approaches to target this process are of relevance. In this context, human amniotic fluid derived stem cells (hAFSC), a class of fetal, pluripotent stem cells with intermediate characteristics between embryonic and adult stem cells, may represent an alternative strategy. hAFSC display immunomodulatory properties, express mesenchymal and embryonic markers, show high proliferation rates, but do not induce tumor formation and their use does not raise ethical issues. Based on these observations, we sought to investigate the effect of hAFSC on CAV in a model of aorta transplantation. Methods: Experimental aorta transplantation was performed using Fisher (F344) rats as donors and Lewis rats as recipients. The abdominal aorta segment, obtained from the emergency of renal arteries until its bifurcation, was orthotopically anastomosed in syngeneic or allogeneic recipients. hAFSC were isolated from amniotic fluid of 16-20 weeks pregnant women, who underwent amniocentesis due to advanced maternal age. Briefly, these cells were cultivated in Dulbecco's modified Eagle's medium-low glucose (DMEM-low) supplemented with 10% fetal bovine serum. hAFSC were purified using their characteristic to adhere to plastic culture dishes, characterized by flow cytometry, and characterized by their potential osteogenic, adipogenic, and chondrogenic differentiation. In addition, RT-PCR experiments demonstrated that these hAFSC express OCT-4 4/5 and NANOG. Rats were divided into 3 groups: syngeneic (SYNG), untreated F344 receiving syngeneic aorta from F344 (n=8); allogeneic (ALLO), Lewis rats receiving allogeneic aorta from F344 (n=8); and ALLO+hAFSC, ALLO rats treated with hAFSC (106 cells) (n=8). Histological analysis and immunohistochemistry were performed 30 days post transplantation. Results: Neointima formation was not observed in the SYNG group. However, the intimal thickness was dramatically increased in the ALLO group accompanied by a high number of ED1+ and CD43+ cells, and enhanced expression of α-SMA in the neointima. Treatment with hAFSC attenuated neointimal thickness and induced a significant decrease of ED1+, CD43+ cells as well as α-SMA expression in the neointima. Table 1: Effects of hAFSC in experimental aortic allograft vasculopathy.Table: No Caption available.Conclusion: These preliminary results showed that hAFSC suppressed inflammation and myofibroblast migration in the intima, possibly through immunomodulatory properties, which may have contributed to ameliorate vascular lesions in CAV.

Impact of Sodium Sulfite (E221) on Chronic Allograft Vasculopathy in Mice

Impact of Sodium Sulfite (E221) on Chronic Allograft Vasculopathy in Mice

Assessment of Longevity of the Direct and Indirect CD4 T Cell Allorecognition Response

Introduction: Recipient CD4 T cells can recognise alloantigen ‘directly’, intact on donor antigen presenting cells (APCs), and ‘indirectly’, as self-restricted processed allopeptide. The relative duration of each pathway remains unclear, and further complicated by our recent description that the longevity of indirect responses differed according to target alloantigen. This work however examined different CD4 T cell responses in different murine models, and to control for differences in the immunogenicity of each, we developed a new model of chronic allograft vasculopathy that would allow definitive examination of all CD4 T cell allorecognition pathways operating in each recipient. Methods: Several mouse strains were intercrossed to generate a novel strain, bm12.Kd.IE, which differs from wild-type B6 by possessing additional MHC class I (H-2Kd) and MHC class II (IAbm12 and IE) molecules, but lacks the IAb MHC class II antigen. Heterotopic cardiac allografts were performed using bm12.Kd.IE donors into B6 recipients, and the model characterised by measuring rejection kinetics, degree of allograft vasculopathy, and production of alloantibody and autoantibody. The relative duration of direct and indirect allorecognition of different alloantigens was assessed by comparing division of monoclonal populations of alloreactive, CFSE-labelled TCR-transgenic CD4 T cells that were adoptively transferred either on day 0 or 28 post transplantation. Indirect allorecognition of MHC I was assessed using TCR75 CD4 T cells (I-Ab-restricted, H2-Kd peptide-specific); class II using TEa CD4 T cells (I-Ab-restricted, I-E peptide-specific) and minor antigen using Mar CD4 T cells (I-Ab-restricted, H-Y peptide-specific). Direct allorecognition of I-Abm12 MHC II was assessed using ABM CD4 T cells. Results: Bm12.Kd.IE hearts survived >50 days in B6 recipients, with histological evidence of chronic allograft vasculopathy and production of anti-Kd and anti-I-E alloantibody. Autoantibody, assessed by indirect immunfluosrescent binding to nuclear-antigen-expressing HEp-2 cells, also developed. Flow cytometric analysis of CFSE labelled transgenic CD4 T cells confirmed that direct pathway responses were robust immediately after transplant, with extensive division of the transferred ABM CD4 T cells, but were minimal four weeks later. Similarly, strong indirect pathway responses against MHC II alloantigen occurred immediately after transplant, but were surprisingly undetectable at later time points. In contrast, indirect alloresponses against MHC I alloantigen were equally strong at early and late times after transplant. Comparable results were obtained when indirect alloresponses against minor H-Y antigen were studied, although division at five weeks was less marked than immediately after transplant. Conclusions: Our results provide experimental evidence to support the paradigm that direct pathway CD4 T cells responses are short-lived, but also highlight that the duration of indirect pathway responses varies according to target alloantigen. The transient nature of anti-class II responses presumably reflects rapid loss of donor APC after transplantation.

Detection of significant coronary artery stenosis with cardiac dual-source computed tomography angiography in heart transplant recipients

Present study evaluates clinical feasibility of cardiac dual-source computed tomography angiography (DSCTA) to detect significant coronary stenosis because of chronic allograft vasculopathy (CAV) after heart transplantation (HTX). An overall of 51 consecutive heart transplant recipients (43 men, 8 women, mean age: 52.3 ± 13.6 years) underwent DSCTA 1 ± 2 days before annual routine invasive coronary angiography (ICA). Three patients were excluded from further analysis. Total 714/717 (99.6%) segments in remaining 48 patients were depicted in diagnostic image quality by DSCTA with three vessel segments in two patients being additionally excluded because of motion artefacts. On a segment-based analysis, sensitivity, specificity, and diagnostic accuracy (DA) for detection of significant stenosis were calculated as 100%, 98.9% and 98.9% respectively. On a patient-based evaluation, sensitivity, specificity and DA were 100%, 86.0% and 93.0% respectively for remaining 46 patients. Negative predictive value (NPV) was 100%. DSCTA enables diagnosis and especially the exclusion of significant coronary artery stenosis in patients after HTX with a high NPV. The low rate of excluded vessel segments compared with former studies indicates improvement in image acquisition and robustness of latest scanner technology and thus may make subsequent annual invasive coronary angiography unnecessary.

352 Role of Mitochondrial Activity in the Development of Chronic Allograft Vasculopathy

This study aimed at investigating the efficacy of dichloracetate (DCA) to prevent the development and progression of chronic allograft vasculopathy (CAV) by regulating the mitochondrial metabolism of aberrant proliferating smooth muscle cells.

ECMO After Prolonged Cardiopulmonary Resuscitation as a Successful Bridge to Immediate Cardiac Retransplant in a 6-Year-Old Girl

Heart failure, life-threatening arrhythmias, and sudden cardiac death are common complications in patients with advanced chronic cardiac allograft rejection--the major limiting factor of long-term survival after heart transplant. In patients with sustained cardiorespiratory arrest refractory to cardiopulmonary resuscitation extracorporeal membrane oxygenation therapy is a therapeutic option. We report the case of a 6-year-old girl with severe chronic allograft vasculopathy who was successfully bridged to cardiac retransplant through extracorporeal membrane oxygenation therapy after prolonged cardiopulmonary resuscitation. Our case demonstrates extracorporeal membrane oxygenation as a rescuing therapeutic option in high-risk, bridge-to-transplant patients, with cardiac arrest. Even after prolonged cardiopulmonary resuscitation, there were no neurologic events, and our patient recovered without any neurologic damage.

A Novel Pathway of Chronic Allograft Rejection Mediated by NK Cells and Alloantibody

Chronic allograft vasculopathy (CAV) in murine heart allografts can be elicited by adoptive transfer of donor specific antibody (DSA) to class I MHC antigens and is independent of complement. Here we address the mechanism by which DSA causes CAV. B6.RAG1(-/-) or B6.RAG1(-/-)C3(-/-) (H-2(b)) mice received B10.BR (H-2(k)) heart allografts and repeated doses of IgG2a, IgG1 or F(ab')(2) fragments of IgG2a DSA (anti-H-2(k)). Intact DSA regularly elicited markedly stenotic CAV in recipients over 28 days. In contrast, depletion of NK cells with anti-NK1.1 reduced significantly DSA-induced CAV, as judged morphometrically. Recipients genetically deficient in mature NK cells (γ-chain knock out) also showed decreased severity of DSA-induced CAV. Direct NK reactivity to the graft was not necessary. F(ab')(2) DSA fragments, even at doses twofold higher than intact DSA, were inactive. Graft microvascular endothelial cells responded to DSA in vivo by increased expression of phospho-extracellular signal-regulated kinase (pERK), a response not elicited by F(ab')(2) DSA. We conclude that antibody mediates CAV through NK cells, by an Fc dependent manner. This new pathway adds to the possible mechanisms of chronic rejection and may relate to the recently described C4d-negative chronic antibody-mediated rejection in humans.

Prevention, inhibition, and reversion of chronic allograft vasculopathy by mitochondrial modulation

Aims: This study aimed at investigating the efficacy of dichloracetate (DCA) to prevent the development and progression of chronic allograft vasculopathy (CAV) by regulating the mitochondrial metabolism of aberrant proliferating smooth muscle cells.

Down-regulation of vascular HMGB1 and RAGE expression by n-3 polyunsaturated fatty acids is accompanied by amelioration of chronic vasculopathy of small bowel allografts

Chronic allograft rejection, which is manifested as chronic allograft vasculopathy (CAV), continues to refrain the long-term success of small bowel transplantation (SBTx). The pathway mediated by the receptor for advanced glycation end products (RAGE) and its ligand, high mobility group box-1 (HMGB1), may contribute to the pathogenesis of CAV, given that they were involved in the process of allograft rejection. n-3 polyunsaturated fatty acids (PUFAs), which have been discovered to attenuate CAV, may have potential impacts on this pathway. The present study investigated whether n-3 PUFAs attenuated CAV via the regulation of the HMGB1-RAGE pathway in a chronic rejection model of rat SBTx. We revealed that the expression of HMGB1 and RAGE was increased in CAV-bearing vessels as well as endothelial cells isolated from these vessels. Oral administration of fish oil with high levels of n-3 PUFAs following SBTx significantly reduced the HMGB1 and RAGE expression, which coincided with the amelioration of CAV. In contrast, feeding of corn oil that contained low levels of n-3 PUFAs had no favorable effects on CAV development and failed to decrease the HMGB1 and RAGE expression. These results indicate that protective effects of n-3 PUFAs on allograft vessels exist via down-regulation of the HMGB1-RAGE pathway.

Late outgrowth endothelial progenitor cells engineered for improved survival and maintenance of function in transplant-related injury

Chronic allograft vasculopathy (CAV) is a major cause of organ transplant failure that responds poorly to treatment. Endothelial activation, dysfunction and apoptosis contribute to CAV, whereas strategies for protecting endothelium and maximizing endothelial repair may diminish it. Late outgrowth endothelial progenitor cells (LO-EPC) can home to areas of injury and integrate into damaged vessels, implying a role in vascular repair; however, in an allograft, LO-EPC would be exposed to the hazardous microenvironment associated with transplant-related ischaemia reperfusion (I/R) injury and persistent inflammation. We evaluated the in vitro effect of I/R injury and the proinflammatory cytokine tumour necrosis factor (TNF)-α on LO-EPC phenotype and function. We show that LO-EPC are intrinsically more tolerant than mature EC to I/R injury induced apoptosis, maintaining their proliferative, migratory and network formation capacity. Under inflammatory conditions, LO-EPC were activated and released higher levels of inflammatory cytokines, upregulated adhesion molecule expression, and were more susceptible to apoptosis. Lentiviral vector-mediated overexpression of the protective gene A20 in LO-EPC maintained their angiogenic phenotype and function, and protected them against TNF-α-mediated apoptosis, reducing ICAM-1 expression and inflammatory cytokine secretion. Administration of ex vivo modified LO-EPC overexpressing A20 might effect vascular repair of damaged allografts and protect from CAV.

Mechanism of arterial remodeling in chronic allograft vasculopathy

Chronic allograft vasculopathy (CAV) remains a major obstacle for long-term survival of grafts even though therapeutic strategies have improved considerably in recent years. CAV is characterized by concentric and diffuse neointimal formation, medial apoptosis, infiltration of lymphocyte or inflammatory cells, and deposition of extracellular matrix both in arteries and veins. Recent studies have shown that stem cells derived from the recipient contribute to neointimal formation under the regulation of chemokines and cytokines. Arterial remodeling in allografts eventually causes ischemic graft failure. The pathogenesis is multi-factorial with both immunologic and non-immunological factors being involved. The immunological factors have been discussed extensively in other articles. This review focuses mainly on the arterial remodeling that occurs in 3 layers of vessel walls including intimal injury, accumulation of smooth muscle-like cells in the neointimal, medial smooth muscle cell apoptosis, adventitial fibrosis, and deposition of extracellular matrix.

Anticardiac Myosin Immunity and Chronic Allograft Vasculopathy in Heart Transplant Recipients

Chronic allograft vasculopathy (CAV) contributes to heart transplant failure, yet its pathogenesis is incompletely understood. Although cellular and humoral alloimmunity are accepted pathogenic mediators, animal models suggest that T cells and Abs reactive to graft-expressed autoantigens, including cardiac myosin (CM), could participate. To test the relationship between CAV and anti-CM autoimmunity in humans, we performed a cross-sectional study of 72 heart transplant recipients: 40 with CAV and 32 without. Sera from 65% of patients with CAV contained anti-CM Abs, whereas <10% contained Abs to other autoantigens (p < 0.05), and only 18% contained anti-HLA Abs (p < 0.05 versus anti-CM). In contrast, 13% of sera from patients without CAV contained anti-CM Abs (p < 0.05; odds ratio [OR], associating CAV with anti-CM Ab = 13, 95% confidence interval [CI] 3.79-44.6). Multivariable analysis confirmed the association to be independent of time posttransplant and the presence of anti-HLA Abs (OR = 28, 95% CI 5.77-133.56). PBMCs from patients with CAV responded more frequently to, and to a broader array of, CM-derived peptides than those without CAV (p = 0.01). Detection of either CM-peptide-reactive T cells or anti-CM Abs was highly and independently indicative of CAV (OR = 45, 95% CI 4.04-500.69). Our data suggest detection of anti-CM immunity could be used as a biomarker for outcome in heart transplantation recipients and support the need for further studies to assess whether anti-CM immunity is a pathogenic mediator of CAV.

KCa3.1 as a potential new target for the prevention of chronic allograft vasculopathy and airway allograft rejection

The Ca+-activated K+ channel KCa3.1 is critically involved in the activation of T cells, macrophages, proliferating vascular smooth muscle cells and fibroblasts. KCa3.1 has therefore been suggested as a potential therapeutic target for diseases where activation and excessive proliferation of one or more of these cell types is involved in the pathology. We here evaluated the KCa3.1 blocker TRAM-34 in two models of chronic allograft rejection. In an obliterative airway disease model, where tracheas from CBA mice were heterotopically transplanted into the greater omentum of C57Bl6 mice, both genetic deficiency and pharmacological blockade of KCa3.1 with TRAM-34 reduced luminal obliteration and significantly suppressed IFN-gamma and IL4 in Elispot assays. We further performed orthotopic aortic transplantations in the PVG-to-ACI rat model and evaluated chronic allograft vasculopathy after 120 days. TRAM-34 dose-dependently reduced aortic luminal occlusion, adventitia area and mononuclear cell infiltration. Its effectiveness was comparable to the m-Tor inhibitor rapamycin (0.3 mg/kg). Our findings suggest that KCa3.1 channels are involved in the pathology of obliterative airway disease, a major complication after lung-transplantation, and chronic allograft vasculopathy, which remains one the major obstacles to long-term functioning of solid organ transplants. Supported by NIH (RO1GM076063)

Acetylcholine and Chronic Vasculopathy in Rat Renal Allografts

Chronic allograft vasculopathy (CAV) is an important aspect of chronic allograft injury, which limits the long-term success of renal transplantation. The pathogenesis of CAV is ill defined, and no effective therapies exist. Acute rejection episodes are a major risk factor for CAV. Recently, we demonstrated that leukocytes, which strongly accumulate in allograft blood vessels during fatal acute rejection, produce acetylcholine (ACh), which has the potential to provoke CAV. Herein, we test the hypothesis that ACh is also produced by leukocytes during the development of CAV. Kidneys were transplanted in the Fischer 344 to Lewis rat strain combination, an established experimental model for CAV. Isografts were performed in Lewis rats. The capacity of intravascular graft leukocytes to synthesize ACh was investigated during reversible acute rejection on day 9 posttransplantation and during the process of vascular remodeling on day 42. Furthermore, allograft recipients were treated with rivastigmine, which blocks enzymatic degradation of ACh. The protein expression of the high-affinity choline transporter-1 and choline acetyltransferase was increased in leukocytes from allografts on day 9 and 42 posttransplantation. In addition, leukocytes accumulating in the lumina of allograft blood vessels were by far more numerous compared with isografts. In line with our hypothesis, ACh itself was detected by high-pressure liquid chromatography in graft leukocytes but not in leukocytes from untreated kidneys. Treatment with rivastigmine drastically exacerbated CAV compared with placebo. We suggest that endogenous ACh contributes to the pathogenesis of CAV and may be a promising target for novel therapies preventing CAV.

Late Renal Allograft Rupture Associated with Cessation of Immunosuppression following Graft Failure

A 29-year-old man developed chronic allograft nephropathy 63 months after renal transplantation. He became symptomatic with advanced chronic graft failure; his immunosuppressive medications were reduced and he was commenced on haemodialysis. Two months following the withdrawal of immunosuppression, he presented with abdominal pain, haematuria, and a marked drop in haemoglobin. The patient was taken to the operating room, where the renal allograft was found to be ruptured, and graft nephrectomy was subsequently performed. Histological examination of the graft specimen showed severe haemorrhagic acute vascular cellular rejection in a background of marked chronic allograft vasculopathy. Immunostaining for C4d showed diffuse, strong, linear circumferential staining of the peritubular capillaries, indicating a concurrent antibody-mediated rejection. We report herein an unusual case of spontaneous renal allograft rupture that occurred long time after transplantation due to severe acute rejection following cessation of immunosuppressive medications for advanced chronic allograft failure. To the best of our knowledge, the time interval between transplantation and the rupture of this allograft is the longest of those reported in the literature.

Antithymocyte Globulin Induction Therapy in Heart Transplantation: Prospective Randomized Study of High vs Standard Dosage

Background In cardiac transplantation, high-dose antithymocyte globulin (ATG) induction therapy as short-term rejection prophylaxis has not been used. Objective To evaluate the efficacy and safety of intraoperative use of single high-dose ATG induction therapy after heart transplantation. Patients and Methods Fourteen patients received single high-dose ATG therapy plus shortened standard therapy (group1), and 16 patients received ATG standard therapy (group2). Results No perioperative deaths were reported. During follow-up, 3 deaths were recorded. Five- year patient survival was 92.8% in groupl vs 85.7% in group2 ( P = .34). The mean (SD) number of acute rejection episodes per patient was 2.5 (2.2) in the high-dose ATG group vs 2.7 (2.5) in the standard therapy group ( P = .83), with 5-year freedom from acute rejection of 45.5% in group 1 vs 35.6% in group 2 ( P = .85). Infections were observed in 6 patients in group1 and in 8 patients in group2 ( P = .69). Malignant disease was diagnosed in 1 patient in the high-dose group and 3 patients in the standard therapy group ( P = .35). Chronic allograft vasculopathy was recognized in 4 patients (28%) in group1 and 8 (50%) in group2 ( P = .05). Five-year actuarial freedom from allograft vasculopathy was 69.2% in the high-dose ATG group vs 50.0%% in the standard therapy group ( P = .35). Conclusions High-dose ATG for prevention of rejection episodes is safe and efficacious, with a lower rate of early and late complications, in particular, graft vasculopathy.

Immunohistochemical characterization of glomerular and tubulointerstitial infiltrates in renal transplant patients with chronic allograft dysfunction

The term chronic allograft nephropathy (CAN) was deleted in the Eighth Banff Classification and two new categories were introduced: chronic T-cell-mediated rejection (CTMR) and chronic active humoral rejection (CAHR). The aim of this study was to revise our CAN cases diagnosed in the last 4 years, analyse allograft survival rates and identify types of infiltrating cells in the different settings. Seventy-nine patients with biopsy-proven CAN were examined and classified into four groups according to the Banff 2005 criteria: CTMR, CAHR, chronic calcineurin inhibitor toxicity (CNITOX) and interstitial fibrosis and tubular atrophy not otherwise specified (NOS). CD4, CD8, CD20, CD68, CD103, Foxp3 and IL-17 protein expression and C4d deposits were investigated. We diagnosed 20 CTMR, 13 CAHR, 28 CNITOX, and 18 NOS. Death-censored graft survival at 4 years from renal biopsy was worse in CAHR compared with the other types of chronic injury. Glomerular CD8(+) cells were increased in CTMR vs CNITOX and NOS. Interstitial CD4(+) and CD8(+) cells were increased in CTMR vs CNITOX. CD68(+) cells in glomerular and peritubular capillaries were higher in CAHR vs CNITOX, CTMR and NOS. CD103(+) cells were higher in cases with tubulitis than in those without. T regulatory and T helper 17 cells were rarely observed in the different settings. Graft survival was worse in patients with CAHR. The presence of any grade transplant glomerulopathy and chronic allograft vasculopathy are poorer prognostic factors. Infiltrating CD8(+), CD103(+) and CD4(+) cells may help to differentiate CTMR from other types of chronic injury, thus improving diagnostic/prognostic features of biopsy in patients with chronic allograft dysfunction.

Donor Age Is Associated With Chronic Allograft Vasculopathy After Adult Heart Transplantation: Implications for Donor Allocation

Chronic allograft vasculopathy (CAV) is a major cause of long-term complications and mortality after heart transplantation. Although recipient factors have been implicated, little is known of the role of donor factors in CAV development. We sought to identify donor factors associated with development of CAV after heart transplantation. We reviewed the United Network for Organ Sharing heart transplant database from August 1987 to May 2008. Univariate and multivariate analyses were performed to assess the association between donor variables and the onset of CAV for adult recipients. Donor age was matched to recipient age and analyzed with respect to development of CAV. Of the 39,704 recipients, a total of 11,714 (29.5%) experienced CAV. Multivariate analysis demonstrated seven donor factors as independent predictors of CAV: age, ethnicity, sex, weight, history of diabetes, hypertension, and tobacco use. When matching young donors (0 to 19.9 years) and old donors (> or =50 years) to each recipient age group, older donors (> or =50 years) conferred a higher risk of developing CAV. Further modeling demonstrated that for each recipient group, older donor age (> or =50 years) conferred a higher risk of CAV development compared with younger donor age (0 to 19.9 years; p < 0.0001). Donor factors including sex, hypertension, diabetes, and tobacco use are independently associated with recipient CAV. Older donor age confers a greater risk of CAV development regardless of the age of the recipient. A heightened awareness for the development of CAV is warranted when using older donors in adult cardiac transplantation, in particular with recipients 40 years of age or older.

Differential Requirement of CD27 Costimulatory Signaling for Naïve Versus Alloantig(en‐Primed Effector/Memory CD8+ T Cells

CD8(+) memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T-cell costimulatory pathway in alloreactive CD8(+)/CD4(+) T-cell activation. CD27-deficient (CD27(-/-)) and wild-type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4(+) or CD8(+) T cells, suggesting that CD27 is not essential during primary T-cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27(-/-) or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor-type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40- but not day 10-sensitized CD27(-/-) recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8(+) T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27(-/-) recipients of class I- but not class II-mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8(+) memory T cells in acute and chronic allograft rejection.