ASIP Highlights Session:
I Am An ASIP Member and This Is My Science
- Experimental Biology 2019 – Orlando FL
Dani S. Zander, MD
MacKenzie Professor and Chair
Department of Pathology and Laboratory Medicine
University of Cincinnati, Cincinnati, OH
By way of background, I am a pathologist who graduated from medical school at the University of Florida, then completed my residency in Anatomic and Clinical Pathology at Cornell and the University of Florida. After graduating from residency, I took a faculty position at the University of Florida with the expectation that I would become the primary pulmonary pathologist for the institution and the primary pathologist responsible for supporting the lung transplantation program. This proved to be a pivotal decision point in my academic career and in my development as a scientist.
Because of my involvement in diagnostic pulmonary pathology, I chose to pursue translational research and focus on the pathogenesis and diagnosis of lung diseases. This has held true throughout my years at the University of Florida, the University of Texas-Houston, Penn State University where I moved to become Chair of the Pathology Department, and finally at the University of Cincinnati where I serve as the Chair of the Pathology and Laboratory Medicine Department.
My work as a member of the lung transplant team in Florida led me to become very interested in transplantation pathology. In my clinical practice, I’d been involved in the diagnosis of hyperacute rejection in a patient receiving a lung transplant. This is a rare and usually fatal complication of lung transplantation and represents a form of humoral rejection that occurs in the first 24 hours following lung transplantation in recipients who have pre-formed anti-HLA antibodies. Fortunately, with improved sensitivity of HLA antibody testing, hyperacute rejection now rarely occurs.
At the University of Florida, we performed a flow cytometry cross-match in 92 lung transplant recipients using serum samples obtained immediately before transplantation, and found that the presence of preformed antibodies was correlated with the incidence of severe graft dysfunction manifested as pulmonary infiltrates and severe hypoxemia with onset in the first few hours after transplantation. Class II, and perhaps class I HLA antibodies at relatively low concentrations represented a risk factor for severe early pulmonary graft dysfunction, with the potential to progress to hyperacute rejection and death.
The causes of early posttransplant death include a variety of complications that can be difficult to distinguish from each other. We looked at the major causes of death during the first 30 days after lung transplantation and found that these included not only antibody-mediated rejection, but also infections, hypoxic-ischemic encephalopathy secondary to cardiac arrest, pulmonary venous thrombosis, and ischemic reperfusion injury. Because these processes often demonstrate overlapping clinical and morphologic features requiring multiple diagnostic techniques for resolution, a systematic multimodality approach to diagnosis is needed, and we published an algorithm to assist in the evaluation of patients with early signs of distress after lung transplantation.
For people who survive the first 30 days after lung transplantation, rejection and infection become the most significant challenges. Chronic rejection is the major cause of longterm graft loss and the most important predisposing factor for chronic rejection is acute rejection, especially if it is high grade and/or recurrent. Rejection is an immunologic process, involving both a cellular and humoral host immunologic response against donor antigens, and leading over time to airway obstruction by scar tissue, which we call obliterative bronchiolitis (OB) or chronic rejection.
Our group sought to better understand the pathobiology of rejection, and to look at possible interventions for rejection in rodent models. We looked at heme oxygenase-1 (HO-1) which had been identified as a graft survival gene in cardiac and liver transplant models. Our laboratory found HO-1 to be increased in human lung allografts with acute cellular rejection (ACR) and in active obliterative bronchiolitis. HO-1 expression was correlated with increased tissue iron and/or ferritin expression and increased inflammatory/oxidant load as measured by myeloperoxidase expression. We hypothesized that the oxidative stress was associated with the rejection process.
Members of our group next used a murine heterotopic airway rejection model to evaluate HO-1 expression in isografts vs allografts, and correlation with rejection. Isografts demonstrated normal histology with minimal HO-1 staining, whereas allografts showed features of human airway rejection (loss of respiratory epithelium, luminal granulation tissue, lymphocytic tracheitis) with increased HO-1 staining in macrophages and mesenchymal cells. HO-1-deficient mice demonstrated a more rapid progression of the tracheal allograft injury as compared with control allografts, and this was associated with a decrease in the anti-inflammatory cytokine, IL-10. Tracheal transplants using IL-10-deficient mice also developed more severe injury, and this was accompanied by a decrease in HO-1 staining. This led us to conclude that deficiency of HO-1 accelerates the development of the obliterative bronchiolitis-like lesion, and that IL-10 may participate in the genesis of HO-1’s effects on the inflammatory processes triggered by allotransplantation.
Using this same tracheal transplant model, our group looked at the effect of the anti-fibrotic agent pirfenidone on the evolution of obliterative bronchiolitis, both alone or in combination with cyclosporine or rapamycin, two commonly used anti-rejection therapies. Compared with untreated controls, pirfenidone-fed mice showed less epithelial cell injury and luminal granulation tissue and fibrosis. Plasma TGF-beta levels and local TGF-beta expression were decreased in the pirfenidone-treated animals, and this may have contributed to the inhibition of the development of the OB-like lesion. Although there was no significant additive effect of pirfenidone in combination with cyclosporine, pirfenidone plus rapamycin demonstrated additive protection against the development of the obstructive airway lesion. Similar findings with pirfenidone have since been reported by others, and pirfenidone has recently begun to receive some evaluation in human lung transplant recipients.
Other research focuses for me have included work on stem cells in the lung, and studies designed to improve the diagnosis of lung diseases. My stem cell studies have looked at the participation of bone marrow derived stem cells in pulmonary repopulation after human lung or bone marrow transplantation. And my diagnostic work has evaluated specific biomarkers to improve diagnosis of mesothelioma, mesenchymal tumors, and some common but difficult to separate types of lung cancers. Most recently, I am participating in a large study evaluating the utility of the new cryobiopsy technique for diagnosis of interstitial lung diseases.
The ASIP has been a great help to me by allowing me to meet successful scientists who advised me about my research and offered me advice about career development. I also enjoy the opportunities to provide similar support to other scientists and aspiring investigators, and to contribute to their success!
- Scornik JC, Zander DS, Baz MA, Donnelly WH, Staples ED. Susceptibility of lung transplants to preformed donor-specific HLA antibodies as detected by flow cytometry. Transplantation. 1999;68:1542-6.
- Zander DS, Baz MA, Visner GA, Staples ED, Donnelly WH, Faro A, Scornik JC. Analysis of early deaths after isolated lung transplantation. Chest. 2001;120:225-32.
- Zhou H, Latham CW, Zander DS, Margolin SB, Visner GA. Pirfenidone inhibits obliterative airway disease in mouse tracheal allografts. J Heart Lung Transplant. 2005;24:1577-85.
- Zander DS, Baz MA, Cogle CR, Visner GA, Theise ND, Crawford JM. Bone marrow-derived stem-cell repopulation contributes minimally to the Type II pneumocyte pool in transplanted human lungs. Transplantation. 2005;80:206-12.
- Visner GA, Faro A, Zander DS. Role of transbronchial biopsies in pediatric lung diseases. Chest. 2004;126:273-80.
- Bonnell MR1, Visner GA, Zander DS, Mandalapu S, Kazemfar K, Spears L, Beaver TM. Heme-oxygenase-1 expression correlates with severity of acute cellular rejection in lung transplantation. J Am Coll Surg. 2004;198:945-52.
- Visner GA, Lu F, Zhou H, Latham C, Agarwal A, Zander DS. Graft protective effects of heme oxygenase 1 in mouse tracheal transplant-related obliterative bronchiolitis. Transplantation. 2003;76:650-6.
- Lu F, Zander DS, Visner GA. Increased expression of heme oxygenase-1 in human lung transplantation. J Heart Lung Transplant. 2002;21:1120-6.
- Zander DS, Baz MA, Massey JK. Patterns and significance of CD44 expression in lung allografts. J Heart Lung Transplant. 1999;18:646-53.
- Vos R, Wuyts WA, Gheysens O, Goffin KE, Schaevers V, Verleden SE, Van Herck A, Sacreas A, Heigl T, McDonough JE, Yserbyt J, Godinas L, Dupont LJ, Neyrinck AP, Van Raemdonck DE, Verbeken EK, Vanaudenaerde BM, Verleden GM. Pirfenidone in restrictive allograft syndrome after lung transplantation: A case series. Am J Transplant. 2018;18:3045-3059.
- von Suesskind-Schwendi M, Heigel E, Pfaehler S, Haneya A, Schmid C, Hirt SW, Lehle K. Protective function of pirfenidone and everolimus on the development of chronic allograft rejection after experimental lung transplantation. Histol Histopathol. 2016;31:793-805.
- Bizargity P, Liu K, Wang L, Hancock WW, Visner GA. Inhibitory effects of pirfenidone on dendritic cells and lung allograft rejection. Transplantation. 2012;94:114-22.
- Visner GA, Liu F, Bizargity P, Liu H, Liu K, Yang J, Wang L, Hancock WW. Pirfenidone inhibits T-cell activation, proliferation, cytokine and chemokine production, and host alloresponses. Transplantation. 2009;88:330-8.
- Dosanjh A. Pirfenidone: a novel potential therapeutic agent in the management of chronic allograft rejection. Transplant Proc. 2007;39:2153-6.
- Dosanjh A. Pirfenidone: anti-fibrotic agent with a potential therapeutic role in the management of transplantation patients. Eur J Pharmacol. 2006;536:219-22.
- Liu H, Drew P, Cheng Y, Visner GA. Pirfenidone inhibits inflammatory responses and ameliorates allograft injury in a rat lung transplant model. J Thorac Cardiovasc Surg. 2005;130:852-8.
- Liu H, Drew P, Gaugler AC, Cheng Y, Visner GA. Pirfenidone inhibits lung allograft fibrosis through L-arginine-arginase pathway. Am J Transplant. 2005;5:1256-63.
- McKane BW, Fernandez F, Narayanan K, Marshbank S, Margolin SB, Jendrisak M, Mohanakumar T. Pirfenidone inhibits obliterative airway disease in a murine heterotopic tracheal transplant model. Transplantation. 2004;77:664-9.