Thoracic Immunobiology Lab

The Thoracic Immunobiology Laboratory studies multiple aspects of thoracic immunology ranging from the alloimmune response after lung transplantation to pulmonary innate immunity and tumor immunology.

Established in 2005, our lab conducts innovative basic and translational research backed by multiple sources of funding, including R01 and T32 grants from the NIH. The lab has three main areas of research focus:

• Innate immune response
• Transplantation immunology
• Tumor immunology

The Thoracic Immunobiology Laboratory is led by Daniel Kreisel, MD, PhD, and Andrew Gelman, PhD, from the Department of Surgery at WashU Medicine, and Alexander Krupnick, MD, from the University of Virginia.

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Principal investigators

Current research

Innate immune response

Neutrophils are critical mediators of innate immunity but tend to be ignored by most scientists as they are thought of as passive “bags” of enzymes that kill pathogens. However, recent work in our laboratory has identified novel mechanisms that protect lungs from neutrophil-mediated injury by regulating the activity of neutrophil bone marrow progenitors. We are also working on uncovering mechanisms through which neutrophils control alloimmune responses as well as how they regulate lung allograft rejection following infection. Our translational work stems from our collaborations with several biotech companies. We are presently involved in the pre-clinical development of inhibitors of toll-like receptors and CD39 and are testing their efficacy in preventing lung graft ischemia-reperfusion injury.

Transplant immunology

Lungs are more immunogenic than other organ and tissue grafts. In the clinical setting, combined heart lung transplants have demonstrated the rapid onset of lung rejection. Recent work in our laboratory has demonstrated that lungs provide a suitable environment for the activation of alloreactive T cells. This sets the lung apart from other organs such as the heart, where initiation of an alloimmune response depends on alloantigen presentation within secondary lymphoid organs. In collaboration with Mark Miller, PhD, Department of Pathology & Immunology, Washington University School of Medicine, we have utilized two-photon microscopy to visualize the encounter between donor antigen-presenting cells and recipient-type T cells early after lung engraftment. Moreover, we have shown that unlike the case for heart transplants, lung rejection does not depend on CD4+ T cells. Thus, requirements for lung rejection are less stringent than for other organs. Our laboratory is currently performing mechanistic studies to elucidate the requirements for T cell activation following lung transplantation. We are also interested in developing modulatory strategies to downregulate immune responses to lung grafts.

Tumor immunology

Cancer remains a leading cause of death in the Western world despite advances in surgical techniques and chemotherapy. Denovo expressed and over expressed of multiple tumor-related antigen could, in theory, serve as a therapeutic target for immune-mediated tumor elimination, but malignancies escape immune recognition and establish tumor-specific tolerance once clinically evident. Our laboratory has focused on understanding the mechanism of tumor tolerance induction and over the last two years has initiated two specific areas of investigation. We are actively studying the role of tumor-associated non-hematopoietic cells, such as vascular endothelium, in the immunologic induction of tolerance to pulmonary metastases. A separate project focuses on immunosurveillance by the innate immune system for primary murine lung cancer. Investigations of lung transplantation, performed in the same laboratory as studies of tumor tolerance induction, offer a unique opportunity to apply principles of allograft rejection to the field of tumor immunology and vice versa. Ready access to human tumor samples from the principal investigator’s clinical practice offers a unique opportunity to perform correlative studies, as well.

Lab alumni

• Xue Lin
• Sara Dehbashi
• Arash Shadman
• Sanjay Murala
• Mikio Okazaki
• Howard Huang
• Seeichiro Sugimoto

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