Expression of Tuberculosis in the Lung (HL-93-12L)
The objective of this program is to encourage research directed at understanding disease expression in the lung following infection with Mycobacterium TB (Mtb). Researchers seek to identify the factors involved in disease expression, to determine relationships among these factors of disease and to better understand how such factors exert their influence on pathogenesis. Studies in humans were encouraged where possible. These basic studies take advantage of new molecular tools and recent developments in cytokine research to study the inflammatory responses occurring in the lung following infection with Mtb. The projects focus mostly on immune responses of the lung to infection. Cell-cell responses and signaling and intracellular events are being examined from different perspectives. Modulation of intracellular killing by alveolar macrophages and the functions of T cell subsets are studied along with the roles of adhesion molecules and networks of activating and deactivating cytokines. Interactions between HIV infection and Mtb are being studied at the cellular level.
The program began in 1993 and continues through 1998; five grants are supported.
R01 HL51631 - Joan Reibman - New York University Medical Center, New York, NY
R01 HL51630 - Elizabeth Rich - Case Western Reserve University, Cleveland, OH
R01 HL51639 - Jesse Roman-Rodriguez - Emory University School of Medicine, Atlanta, GA
R01 HL51636 - Zahra Toossi - Case Western Reserve University, Cleveland, OH
R01 HL51749 - Simon R. Carding - University of Pennsylvania, Philadelphia, PA
Recent Progress
Investigators have found that Mtb upregulates expression of intercellular adhesion molecules but not vascular adhesion molecules. The differences in expression and regulation of these molecules are being examined and it has been found that Mtb enhances expression of ICAM-1 on monocytic cells. Another researcher used immunohisto-chemical techniques to demonstrate increased deposition of fibronectin and collagen around necrotizing granulomas in lung sections from patients with tuberculosis and in animal models. The role of fibronectin is being investigated and it has been found that extra cellular matrix molecules, including fibronectin, affect immune cell activation and cytokine expression, specifically by inducing the proinflammatory cytokine IL-1 . Others have learned that alveolar macrophages are more effective at inhibiting growth of Mtb than blood monocytes. Related work is looking at TB-HIV interactions and why, in cell cultures, HIV grows more rapidly in monocytes from persons with active tuberculosis. The molecular basis for this is being examined. There is growing evidence that the lymphocyte response to Mtb is very specific to mycobacterial antigens. The populations of and lymphocytes involved in the immune response to Mtb are being investigated. It has been learned that in healthy people previously exposed to Mtb vigorous T cell and immune responses develop. In contrast, there is a significant decrease in the number of mycobacteria-reactive T cells (the T cells) from both blood and lung washings of patients with active tuberculosis. Proposed mechanisms for the decrease in T cells include hyporesponsiveness and activation-induced cell death (apoptosis).
With the collaboration of the NICHD and the NIAID, the NHLBI is conducting a phase II/III randomized, double-blind controlled study of HIVIG for the prevention of HIVIG for the prevention of HIV transmission from HIV-infected pregnant women to their fetuses and newborns receiving ZDV. Both newborns and mother receive ZDV. Enrollment started in July 1993 and the study is expected to enroll 800 mother/infant pairs.
The following Principal Investigators and their institutions are participating in recruiting patients:
Martin Lepow - Albany Medical Center, Albany, NY
William Shearer - Baylor College of Medicine, Houston, TX
James Oleske - University of Medicine & Dentistry, NJ, Newark, NJ
Andrea Kovacs - Los Angeles City/USC Medical Center, Los Angeles, CA
Henry Sacks - Mt. Sinai School of Medicine, New York, NY
William Borkowsky - New York University Medical Center, New York, NY
Diane Wara - San Francisco General Hospital, San Francisco, CA
Diane Wara - University of California, San Francisco, CA
Eleanor Jimenez - San Juan Hospital, San Juan, PR
Patricia Flynn - St. Jude Children's Hospital, Memphis, TN
Patricia Flynn - Regional Medical Center of Memphis, Memphis, TN
Patricia Flynn - Methodist Hospital of Memphis, TN
Myron Levin - UCHSC - Childrens Hospital of Denver, Denver, CO
Myron Levin - Denver General Hospital, Denver, CO
Richard Stiehm - UCLA Medical Center, Los Angeles, CA
Stephen Spector - University of California - San Diego, LaJolla, CA
Kenneth Rich - University of Illinois at Chicago, Chicago, IL
Janet Squires - Univ. of Texas, Southwestern Medical Center., Dallas, TX
Sohail Rana - Howard University Hospital, Washington, DC
Jane Pitt - Columbia Presbyterian, Medical Center, New York, NY
Maggie Silio - Tulane - LSU Pediatric AIDS Clinical Trials Unit, New Orleans, LA
Maggie Silio - University Hospital Medical Center of LA, New Orleans, LA
Celementine Diaz - Univ. of Puerto Rico, School of Medicine, San Juan, PR
Rosaura Aguayo - Dr. Ramon Ruiz Arnau, University Hospital, Bayamon, PR
William Borkowsky - New York University Medical Center, New York, NY
Gwendolyn Scott - University of Miami School of Medicine, Miami, FL
Margaret Keller - Harbor UCLA Medical Center, Torrance, CA
William Durbin - University of MA Medical Center, Worcester, MA
Philip Toltzis - Case Western University Hospitals of Cleveland, OH
Sandra Burchett - Children's Hospital, Boston, MA
Sandra Burchett - Brigham & Women's Hospital, Boston, MA
Stephen Pelton - Boston Medical Center, Boston, MA
Andrea Ruff - Johns Hopkins University Hospital, Baltimore, MD
Peter Vink - University of Maryland, Baltimore, MD
Wilma Lim - University of NC at Chapel Hill, Chapel Hill, NC
George Johnson - Medical University of SC, Charleston, SC
Leonard Weiner - SUNY Syracuse, Syracuse, NY
Sharon Nachman - SUNY Stony Brook, Stony Brook, NY
Duane Harrison - Hutzel Hospital/Children's Hospital of Michigan, Detroit, MI
Marilyn Crain - University of Alabama, Birmingham, AL
Mobeen Rathore - University of FL Health, Science Center, Jacksonville, FL
Stuart Starr - Children's Hospital of Philadelphia, PA
Jeffrey Merrill - Hospital University of PA, Philadelphia, PA
Susan Adeniyi-Jones - Tomas Jefferson University Hospital, Philadelphia, PA
Harold Lischner - St. Christopher's Hospital for Children, Philadelphia, PA
Harold Lischner - Temple University Hospital, Philadelphia, PA
Lisa Frenkel - Children's Hospital and Medical Center, Seattle, WA
Andrew Wizniz - Bronx Lebanon Hospital, Bronx, NY
Tamara Rakusan - Children's National Medical Center, Washington, DC
Tamara Rakusan - Washington Hospital Center, Washington, DC
Thomas Rubio - Children's Hospital of the Kings Daughters, Norfolk, VA
Thomas Rubio - Sentara Norfolk General, Norfolk, VA
Barbara Stechenberg - Baystate Medical Center, Springfield, MA
Peter Krause - University of CT Health Center, Hartford, CT
Due to the nature of this clinical trial (double-blinded, placebo-controlled) data analyses is still pending enrollment and follow-up of all participants. Therefore, data is not available at this point in time.
This award is aimed at improving coordination of TB curricula at funded institutions. Examples include: development of a problem-based learning module on TB for second-year medical students, a medical student summer TB research project, and mentored clinical rotations focusing on TB control procedures. Other activities include neighborhood health worker training, assessment of current pre-clinical knowledge about TB possessed by medical students and didactic lectures on TB epidemiology.
This program supports 24 awards, 6 started in fiscal year 1993, 6 started in fiscal year 1994, 4 started in fiscal year 1995, 4 started in 1996, and 5 started in 1997. Each award lasts for five years.
The following awards started in fiscal year 1993.
K07 HL03015 - Lee Reichman - University of Medicine & Dentistry, Newark, NJ
K07 HL03020 - Sally Hodder - Case Western Reserve University, Cleveland, OH
K07 HL03032 - Jeffrey Starke - Baylor College of Medicine, Houston, TX
K07 HL03034 - Michael Johnson - Johns Hopkins University, Baltimore, MD
K07 HL03065 - Antonino Catanzaro - University of California, San Diego, CA
K07 HL03078 - Henry Blumberg - Emory University, Atlanta, GA
The following awards started in fiscal year 1994.
K07 HL03013 - Matthew Levison - Medical College of Pennsylvania, Philadelphia, PA
K07 HL03030 - Neil Schluger - New York University Medical Center, New York, NY
K07 HL03044 - Karen Bruoney - Columbia University, New York, NY
K07 HL03057 - Charles Daley - University of California, San Francisco, CA
K07 HL03251 - Nancy Dunlap - University of Alabama at Birmingham, AL
K07 HL03259 - Ricardo Gonzalez-Rothi - University of Florida, Gainesville, FL
The following awards started in fiscal year 1995.
K07 HL03329 - Sandra Willsie - University of Missouri, Kansas City, MO
K07 HL03332 - Arthur Pitchenik - University of Miami, Miami, FL
K07 HL03335 - Gail Woods - University of Texas, Galveston, TX
K07 HL03330 - Henry Yeager - Georgetown University, Washington, DC
The following awards started in fiscal year 1996.
K07 HL03035 - John Bernardo - Boston Health & Hospitals, Boston, MA
K07 HL03327 - Juzar Ali - LA State University Medical Center, New Orleans, LA
K07 HL03585 - Patrick Brennan - University of Pennsylvania, Philadelphia, PA
K07 HL03591 - Gary Kalkut - Montefiore Medical Center, New York, NY
The following awards started in fiscal year 1997.
KO7 HL03588 - William Rodriguez - University of Puerto Rico, San Juan, PR
KO7 HL03752 - Brenda Jones - University of Southern California, Los Angeles, CA
KO7 HL03759 - Carol Hamilton - Duke University Medical Center, Durham, NC
KO7 HL03583 - Thomas Bailey - Washington University Medical Center, St. Louis, MO
KO7 HL03761 - Edward Nardell - Harvard Medical School, Boston, MA