Clinical Pathophysiology Section
John I. Gallin, M.D.
Head, Clinical Pathophysiology Section
Director, Clinical Center NIH
Dr. Gallin's research focuses on the immunopathogenesis of chronic granulomatous disease (CGD), Job's syndrome, leukocyte adhesion deficiency,
and other diseases relating to primary neutrophil dysfunction. Douglas Kuhns, Ph.D., of SAIC Frederick, implements an important component of
the basic science program of this section with a focus on function and intracellular signaling pathways of neutrophils, leading to the
production of reactive oxygen species and the chemokine interleukin-8. Kol Zarember, Ph.D., Research Associate, studies mechanisms by
which neutrophils kill pathogenic microorganisms.
Description of Research Program
The Clinical Pathophysiology Section conducts long-term studies of the natural history and pathogenesis of diseases caused by abnormal phagocyte function. Our studies include patients with CGD of childhood, hyperimmunoglobulin E-recurrent infection syndrome (Job's), leukocyte adhesion deficiency, and those with recurrent infections that do not fall into a specifically defined disease category. Specific studies analyze the function of phagocytic cells and the production of cytokines such as IL-8.
The section emphasizes studies of the etiology, pathogenesis, and therapy of granulomatous disorders caused by an inherited defect in the ability of phagocytes (neutrophils and monocytes) to produce superoxide. This defect leads to recurrent, life-threatening bacterial and fungal infections as well as tissue granuloma formation.
The phagocyte-stimulating cytokine interferon-gamma has been shown to reduce the frequency and severity of infections in CGD. We have created a mouse model of the most common autosomal recessive form of CGD. This knockout mouse faithfully mimics the human disease and is being used to study the multiple roles of superoxide in the inflammatory process and other processes. The effects and mechanisms of cytokines in this setting also are studied.
Our research also aims to understand and enhance the host factors responsible for resistance to mycobacteria. These goals are being pursued through study of the macrophage responses of patients with susceptibility to low-level mycobacterial pathogens such as Mycobacterium avium complex. In addition, we are treating patients with mycobacterial infections with IFN-gamma to enhance mycobacterial killing.
Another series of projects focuses on the eosinophil, an enigmatic white blood cell that seems to cause as much harm (allergy, asthma) as it
does good. Among the toxic proteins carried by the eosinophil are two proteins—the eosinophil cationic protein (ECP) and eosinophil-derived
neurotoxin (EDN)—that are also enzymatically active ribonucleases. We are attempting to understand this puzzle of biochemistry and
physiology—how the ribonuclease activity and toxicity are related—as we believe this will ultimately lead to a better understanding of
the role of the eosinophil in the human body.
Research Award of the American Federation for Clinical Research, Squibb Award, Infectious Disease Society of America, Honorary Doctor of Science (Amherst College), Jeffrey Modell Foundation Lifetime Achievement Award, Elected to the Institute of Medicine of the National Academy of Sciences
Research Group Members
Dr. Douglas Kuhns, Dr. Kol Zarember.
Selected Recent Publications
To view a complete listing, visit PubMed.
Lekstrom-Himes JA, Kuhns DB, Alvord WG, Gallin JI. Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease. J Immunol. 2005. 174(1): 411-417.
Medvedev AE, Lentschat A, Kuhns DB, Blanco JC, Salkowski C, Zhang S, Arditi M, Gallin JI, Vogel SN. Distinct mutations in IRAK-4 confer hyporesponsiveness to lipopolysaccharide and interleukin-1 in a patient with recurrent bacterial infections. J Exp Med. 2003. 198(4): 521-531.
Gallin JI, Alling DW, Malech HL, Wesley R, Koziol D, Marciano B, Eisenstein EM, Turner ML, DeCarlo ES, Starling JM, Holland SM. Itraconazole to prevent fungal infections in chronic granulomatous disease. N Engl J Med. 2003. 348(24): 2416-2422.
Kuhns DB, Nelson EL, Alvord WG, Gallin JI. Fibrinogen induces IL-8 synthesis in human neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine or leukotriene B(4). J Immunol. 2001. 167(5): 2869-2878.
Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL. Treatment of chronic granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted hematopoietic allograft. N Engl J Med. 2001. 344(12): 881-888.
Lekstrom-Himes JA, Gallin JI. Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med. 2000. 343(23): 1703-14.
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