Kenneth Cooke, M.D.
Assistant Professor
Pediatrics and Communicable Diseases
Division of Hematology/Oncology
krcooke@umich.edu

During the last several decades, allogeneic bone marrow transplantation (i.e. the transplantation of bone marrow from a donor other than "self") has emerged as an important therapy for a number of malignant and non-malignant diseases. Specifically, allogeneic bone marrow transplantation (BMT) is now accepted as the treatment of choice for adults with chronic myeloid leukemia (CML), and in adults and children with acute myeloid leukemia (AML) in first remission or who have acute lymphoid leukemia (ALL) with high-risk features or relapsed disease. Unfortunately, the utility of this treatment strategy is limited by several serious side effects, including the development of graft versus host disease (GVHD) and pulmonary toxicity. As the term implies, GVHD refers to a disease state where in T lymphocytes from the donor bone marrow "graft" attack tissues of the "host" which are recognized as foreign. The onset of GVHD is typically within the first several weeks after transplantation and classic target organs include the skin, gastrointestinal tract, and liver. Recently, the lung has been recognized as a potential target of this immunologically mediated attack. In almost half of the pneumonias that occur after BMT a specific infection can NOT be found, and are referred to as idiopathic pneumonia syndrome (IPS). Although an association between lung injury without infection (IPS) and GVHD has been reported, a true relationship between the two entities has not been clearly established. Utilizing well-established mouse models of allogeneic BMT, I have investigated the potential causes of IPS. Data generated thus far support the hypothesis that the lung is a target organ of the graft versus host reaction. Significant progress has been made in identifying two interrelated pathways of lung injury and this information has paved the way for two clinical protocols wherein agents used initially in the laboratory are being used to treat our patients who have developed lung injury after BMT. My laboratory studies is currently interested in understanding the mechanisms responsible for donor leukocyte recruitment to the inflamed lung and studies are focusing on the role of chemokines and cellular adhesion molecules.

Representative Publications

Original Contributions
1. Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte Jr, J, Crawford JM, and Ferrara, JLM. (1996) An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: The roles of minor H antigens and endotoxin. Blood, 88, 3230-3239.

2. Cooke, KR, Nishinakamura, R, Martin, TR, Kobzik, L, Brewer, J, Whitsett, JA, Bungard, D, Murray, R, and Ferrara, JLM. (1997) Persistence of pulmonary pathology and abnormal lung function in IL-3/GM-CSF/IL-5 bc receptor deficient mice despite correction of alveolar proteinosis after BMT. Bone Marrow Transplantation, 20, 657-662.

3. Cooke, KR, Krenger, W, Hill, G, Martin, TR, Kobzik, L, Brewer, J, Simmons, R, Crawford, JM, Van den Brink, M, and Ferrara, JLM. (1998) Host reactive donor T cells are associated with lung injury after experimental allogeneic BMT. Blood, 92, 2571-2580.

4. Cooke, KR, Hill, GR, Crawford, JM, Bungard, D, Brinson, YS, Delmonte Jr, J, and Ferrara, JLM. (1998) TNF_ production to LPS stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. The Journal of Clinical Investigation, 102, 1882-1891.

5. Cooke, KR, Hill, GR, Gerbitz, A, Kobzik, L, Martin, TR, Crawford, JM, Brewer, J, and Ferrara, JLM. (2000) TNFa neutralization reduces lung injury after experimental allogeneic bone marrow transplantation. Transplantation, 70, 272-279.

6. Cooke, KR, Hill, GR, Gerbitz, A, Kobzik, L, Martin, TR, Crawford, JM, Brewer, JP, and Ferrara, JLM. (2000) Responsiveness of donor accessory cells to LPS stimulation reduces the severity of experimental idiopathic pneumonia syndrome. The Journal of Immunology, 165, 6612-6619.

7. Cooke, KR, Gerbitz, A, Hill, GR, Crawford, JM, Teshima, T, Hill, GR, Tesolin, A, Rossignol, DP, and Ferrara, JLM. (2001) LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. The Journal of Clinical Investigation, 7, 1581-1589.

8. Teshima, T, Ordemann, R, Reddy, P, Gagin, S, Liu, C, Cooke, KR, and Ferrara, JLM. (2002) Expression of MHC II alloantigens on host target tissues is not required for CD4-mediated acute graft-versus-host disease. Nature Medicine, 8, 575-581.

9. Yanik, G, Hellerstedt, B, Custer, J, Hutchinson, R, Ferrara, JLM, Kwon, D, Uberti, J, and Cooke, KR. (2002) Etanercept as a novel therapy for Idiopathic Pneumonia Syndrome after allogeneic bone marrow transplantation. Biology of Blood and Marrow Transplantation, 8, 395-400.

10. Cooke, KR, Olkiewicz, K, Erickson, N, and Ferrara, JLM. (2002) The role of endotoxin and the innate immune response in the pathophysiology of acute graft-versus-host disease. The Journal of Endotoxin Research, 8, 441-448.

11. Duffner, U, Lu, B, Teshima, T, Williams, DL, Hildebrandt, G, Reddy, P, Ordemann, R, Lowler, K, Liu, C, Cooke, KR, and Ferrara JLM. (2003) CXCR3 dependent donor T cell migration during acute GVHD. Experimental Hematology, 10, 897-902.

12. Ojielo, CI, Cooke, KR, Mancuso, P, Standiford, TJ, Olkiewicz, KM, Toews, GB, and Moore, B. (2003) Defective phagocytosis and clearance of pseudomonas aeruginosa in the lung following bone marrow transplantation. The Journal of Immunology,171, 416-424.

13. Hildebrandt, GC, Duffner, UA, Olkiewicz, KM, Willmarth, NE, Corrion, LA, Clouthier, S, Williams, DL, Moore, BB, Kuziel, WA, Liu, C, Yanik, G, and Cooke, KR. (2004) A Critical Role for CCR2 in the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation. Blood, 103, 2417-2426.

14. Duffner U, Maeda Y , Cooke KR , Reddy P, Ordemann R, Liu C, Ferrara JLM, Teshima T. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. The Journal of Immunology. 2004;172:7393-7398.

15.. Gerbitz A, Ewing P, Wilke A, Schubert T, Eissner G, Dietl B, Andreesen R, Cooke KR , Holler E. Induction of heme oxygenase-1 before conditioning results in improved survival and reduced graft-versus-host disease after experimental allogeneic bone marrow transplantation. Biology of Blood and Marrow Transplantation. 2004;10:461-472.

16. Hildebrandt GC, Olkiewicz KM, Corrion LA, Chang Y, Clouthier S, Liu C, Cooke KR . Donor-derived tumor necrosis factor-alpha regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation. Blood. 2004;104:586-593.

17. Hildebrandt GC, Corrion LA, Olkiewicz KM, Lu B, Lowler K, Duffner U, Moore BB, Kuziel WA, Liu C, Cooke KR . Blockade of CXCR3 receptor: Ligand interactions reduces leukocyte recruitment to the lung and the severity of experimental idiopathic pneumonia syndrome. The Journal of Immunology. 2004; 173:2050-2059.

18. Gerbitz A, Nickoloff B, Olkiewicz KM, Willmarth NE, Corrion LA, Hildebrandt GC, Kobzik L, Eissner G, Holler E, Ferrara JLM, Cooke KR. A role for tumor necrosis factor-alpha mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome. Transplantation. 2004;78:494-502.

19. Gerbitz A, Ewing P, Olkiewicz K, Willmarth NE, Williams D, Hildebrandt G, Wilke A, Liu C, Eissner G, Andreesen R, Holler E, Guo R, Ward PA, Cooke KR . A role for CD54 (intercellular adhesion molecule-1) in leukocyte recruitment to the lung during the development of experimental idiopathic pneumonia syndrome. Transplantation, 2005 Mar 15;79:536-42.

20. Hildebrandt GC, Olkiewicz KM, Choi S, Corrion LA, Serody JS, Clouthier S, Liu C, Cooke KR . Do nor T cell production of RANTES significantly contributes to the development of experimental idiopathic pneumonia syndrome after allogeneic stem cell transplantation. (Plenary Paper) Blood, 2005; 105:2249-2257.

21. Uberti, JP., Ayash, L., Ratanatharathorn, V., Silver, S., Reynolds, C., Becker, M., Reddy, P., Cooke, KR ., Yanik, G., Whitfield, J., Jones, D., Hutchinson , R., Braun, T., Ferrara , JLM., and Levine, JE. Pilot trial on the use of etanercept and methylprednisolone as primary treatment for acute graft-versus-host disease. Biology of Blood and Marrow Transplantation, In press.