Genes and Gene Products as Immuno-Adjuvants

Holland, S M.

Abstract

This project is directed at understanding, characterizing, and evaluating the role of cytokines in the pathophysiology and treatment of infectious diseases. We have used mycobacterial diseases as the system in which to examine the role of cytokines and cellular interactions, especially those of the monocyte/macrophage, in the generation of an effective granulomatous response. We hope to determine the nature of the effective granulomatous response and thereby begin to dissect out conditions in which the granulomatous response is ineffective (e.g., tuberculosis) or inappropriate (e.g., sarcoid, Crohn's disease). We have characterized a family with ineffective granulomatous inflammation as demonstrated by disseminated Mycobacterium avium infection in the absence of HIV infection. These patients have low interferon gamma production due to interleukin-12 deficiency. The determination of interleukin-12 deficiency in an infectious disease confirms the role of interleukin-12 in the control of intracellular infections in humans. We have described other patients with low interferon gamma production not due to interleukin-12 deficiency, indicating that the interferon gamma generating pathway is complex. We have successfully treated these patients with subcutaneous interferon gamma. Interferon gamma is now being used in the treatment of multiple- drug resistant tuberculosis.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000647-04
• Application #: 5200547
• Support Year: 4
• Fiscal Year: 1995

Institution

• Name: National Institute of Allergy and Infectious Diseases
• Country: United States

Publications

Xie, Yingda L; Rosen, Lindsey B; Sereti, Irini et al. (2016) Severe Paradoxical Reaction During Treatment of Disseminated Tuberculosis in a Patient With Neutralizing Anti-IFN? Autoantibodies. Clin Infect Dis 62:770-773

Spinner, Michael A; Ker, Jennifer P; Stoudenmire, Charles J et al. (2016) GATA2 deficiency underlying severe blastomycosis and fatal herpes simplex virus-associated hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol 137:638-40

Uzel, Gulbu; Sampaio, Elizabeth P; Lawrence, Monica G et al. (2013) Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol 131:1611-23

Palmore, Tara N; Shea, Yvonne R; Conville, Patricia S et al. (2009) ""Mycobacterium tilburgii,"" a newly described, uncultivated opportunistic pathogen. J Clin Microbiol 47:1585-7

Zelazny, Adrian M; Root, Jeremy M; Shea, Yvonne R et al. (2009) Cohort study of molecular identification and typing of Mycobacterium abscessus, Mycobacterium massiliense, and Mycobacterium bolletii. J Clin Microbiol 47:1985-95

Elloumi, Houda Zghal; Holland, Steven M (2008) Complex regulation of human cathelicidin gene expression: novel splice variants and 5'UTR negative regulatory element. Mol Immunol 45:204-17

Sampaio, Elizabeth P; Elloumi, Houda Z; Zelazny, Adrian et al. (2008) Mycobacterium abscessus and M. avium trigger Toll-like receptor 2 and distinct cytokine response in human cells. Am J Respir Cell Mol Biol 39:431-9

Uzel, Gulbu; Tng, Emilia; Rosenzweig, Sergio D et al. (2008) Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood 111:209-18

Freeman, Alexandra F; Holland, Steven M (2008) The hyper-IgE syndromes. Immunol Allergy Clin North Am 28:277-91, viii

Holland, Steven M (2007) Interferon gamma, IL-12, IL-12R and STAT-1 immunodeficiency diseases: disorders of the interface of innate and adaptive immunity. Immunol Res 38:342-6