Association of Viral Genome with Graft Loss in Children after Cardiac Transplantation

Shirali, Girish S; Ni, Jiyuan; Chinnock, Richard; Johnston, Joyce K.; Rosenthal, Geoffrey L.; Bowles, Neil E.; Towbin, Jeffrey A.

doi:10.1056/nejm200105173442002

Cited by 183 publications

(139 citation statements)

References 29 publications

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“…Prospective protocols to track viral symptoms and identify virus with polymerase chain reaction-based assays have demonstrated a much higher incidence of respiratory viral infection (0.66-1.56 infections per patient-year of follow-up) (35)(36)(37). Likewise, the detection of viral genomes in human cardiac and renal allografts has been increased using polymerase chain reaction-based technology, and the detection of viral genomes in these allografts is also associated with chronic allograft dysfunction (38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Mikols

Yan

Norris

et al. 2006

Am J Respir Crit Care Med

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Rationale: Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction. Objectives: We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection. Methods: Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition. Results: In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation. Conclusions: These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

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Section: Discussionmentioning

confidence: 99%

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

Mikols

Yan

Norris

et al. 2006

Am J Respir Crit Care Med

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“…More recently, endomyocardial biopsies from pediatric heart transplant patients were examined for the presence of viral genomes including adenovirus, herpes simplex, CMV and results correlated with outcome measures including graft loss, acute rejection and CAV (44). The presence of an adenovirus genome was associated with a sixfold increase in risk for CAV, suggesting an important role for viral infection in progression to CAV in pediatric patients.…”

Section: Epidemiological Evidence For Implicating CMV and Other Virusmentioning

confidence: 99%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

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“…Although the pathophysiology of CAV is not completely elucidated, research suggests that graft rejection plays an important role in the evolution of the disease, and the extent of rejection may predict the subsequent development of CAV (5,9). Opportunistic viral infections including cytomegalovirus (CMV) may also be associated with the development of vasculopathy (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Drug Monitoring for Everolimus in Heart Transplant Recipients Based on Exposure–Effect Modeling

Starling¹,

Hare

Hauptman

et al. 2004

American Journal of Transplantation

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Everolimus, a proliferation signal inhibitor, is an immunosuppressant that targets the primary causes of progressive allograft dysfunction, thus improving the long-term outcome after heart transplantation. The present study investigated whether therapeutic drug monitoring (TDM) of everolimus would benefit heart transplant patients. Data from a twelve-month phase III trial comparing everolimus (1.5 or 3 mg daily) with azathioprine were used to evaluate everolimus pharmacokinetics, exposure-efficacy/safety and TDM prognostic simulations. Everolimus trough levels were stable in the first year post-transplant and averaged 5.2 ± 3.8 and 9.4 ± 6.3 ng/mL in patients treated with 1.5 and 3 mg/day, respectively. Cyclosporine trough levels were similar in all treatment groups. Biopsy-proven acute rejection (BPAR) was reduced with everolimus trough levels ≥3 ng/mL. Intravascular ultrasound (IVUS) analysis showed evidence of reduced vasculopathy at 12 months with increasing everolimus exposure. Unlike cyclosporine, increasing everolimus exposure was not related to a higher rate of renal dysfunction. The TDM simulation, which was based on two everolimus dose adjustments and an initial starting dose of 1.5 mg/day, showed that the simulated BPAR rate (with TDM) was 21% versus 26% in the group with fixed dosing. Therefore, TDM in heart transplantation could optimize immunosuppressive efficacy and reduce treatment-related toxicity.

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Association of Viral Genome with Graft Loss in Children after Cardiac Transplantation

Abstract: Identification of viral genome, particularly adenovirus, in the myocardium of pediatric transplant recipients is predictive of adverse clinical events, including coronary vasculopathy and graft loss.

Cited by 183 publications

References 29 publications

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

IL-12 p80 Is an Innate Epithelial Cell Effector That Mediates Chronic Allograft Dysfunction

The Role of Viruses in Cardiac Allograft Vasculopathy

Therapeutic Drug Monitoring for Everolimus in Heart Transplant Recipients Based on Exposure–Effect Modeling

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