AIDS is characterized by opportunistic infections and neoplasms, such as Kaposi's sarcoma. In addition, AIDS patients frequently experience hematologic abnormalities such as bone marrow dysplasia, anemia, thrombocytopenia and leukopenia. These hematologic abnormalities contribute to worsening the patient's condition and also limit the use of antibacterial as well as anti-viral agents. The exact mechanism by which HIV-1 contributes to these characteristic cytopenias are presently unknown and are the research of this program.
This program supports 6 grants and was initiated jointly with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Support continues through 1999.
The following grants are supported by NHLBI.
R01 HL53703 - Robert Means - University of Cincinnati, Cincinnati, OH
R01 HL53744 - Lee Ratner - Washington University, St. Louis, MO
R01 HL53745 - Jerome Groopman - New England Deaconess, Boston, MA
R01 HL53752 - Richard O'Reilly - Sloan-Kettering Institute for Cancer, New York,
NY
R01 HL53754 - Harris Goldstein - Albert Einstein College of Medicine, New York,
NY
R01 HL53737 - Jeanette Mladenovic - University of Colorado Health Science Ctr,
Denver CO
EBV associated lymphoproliferative disorders represent a frequently lethal complication of profound deficiencies of cell mediated immunity in marrow allograft recipients and AIDS patients. Current therapy for these EBV lymphomas is poor. An NHLBI grantee's recent demonstration that transfer of immune T cells from someone else can induce durable regressions of EBV disease in marrow allograft recipients. This ability to "turn the disease around" can be induced rapidly following infusion of immune T cells which suggest that this approach may also have potential as a treatment for such complications in patients with AIDS. However, in such patients, it is highly unlikely that immune T cells can be recruited from themselves. Thus, the development of efficient techniques for the identification, propagation and control of these immune cells transferred from someone else, is very important. This investigator is attempting to find out more about these cells by studying patients and employing a mouse model that will help answer these questions. These studies will likely provide essential information needed for the development of new ways to treat lethal EBV associated disorders in AIDS patients, and may also suggest how these strategies might be effectively used to enhance resistance to the AIDS virus itself.
In the past, the NHLBI supported research efforts that resulted in a solvent/detergent procedure to inactivate viruses in plasma derivatives. The procedure proved highly effective in the inactivation of HIV and hepatitis B and C viruses and is now licensed in countries throughout the World. However, this procedure cannot be utilized in cellular blood components such as red cells and platelets because it harms the cells. Therefore, the Institute is supporting a research program to inactivate infectious agents in cellular blood components.
Recent progress in inactivating viruses in plasma derivatives has been highly successful. Safe and efficient inactivation procedures have been developed and are now widely available. One of these methods, which was developed with NHLBI support, involves treating material with organic solvent and detergent. This approach has been applied successfully to coagulation factor concentrates, immune globulins, lymphokines and other growth factors. Plasma derivatives treated with solvent/detergent mixtures are now prepared in over 14 countries. Derivatives that are manufactured in this way have shown no evidence of transmission of Hepatitis B virus (HBV), Hepatitis C virus (HCV), or human immunodeficiency virus (HIV) in studies designed to monitor the transmission of these agents.
Although significant progress was made in an earlier NHLBI-supported study to develop inactivation procedures, additional research is urgently needed to better understand the mode of action of virucidal reagents and procedures so as to apply and optimize their use in a blood banking environment. Furthermore, studies on the removal of viruses from biological materials in ways that permit the treated products to be used clinically are also needed and are an important goal of this new program.
This program supports 6 grants and will continue through 1999.
R01 HL53357 - Gary Wiesehahn - Steritech, Inc., Concord, CA
R01 HL53380 - David Cook - Steritech, Inc., Concord, CA
R01 HL53384 - Girish Vyas - University of California, San Francisco
R01 HL53418 - Stephen Wagner - ARC, J. H. Holland Laboratory, Rockville,
MD
R01 HL53585 - Robert Floyd - OK Medical Res. Foundation, Oklahoma City,
OK
R01 HL53379 - Daniel Meruelo - New York Medical Center, New York, NY
One of these investigators developed a photochemical treatment which inactivates a broad spectrum of viruses and bacteria in platelet concentrates while maintaining the efficacy of the platelets. In addition, this photochemical treatment destroys leukocytes that invariably contaminate platelet units and cause serious graft-versus-host disease in some recipients. The therapeutic efficacy of the photochemically-treated platelets is currently being evaluated in clinical trials in thrombocytopenic patients requiring platelet transfusions. Other investigators in this program are actively pursuing other approaches to sterilize a different cellular component, red blood cells, in order to further improve the safety of transfusion therapy.
Hemophilia is a hereditary bleeding disorder that results from a deficiency in either blood coagulation protein Factor VIII or Factor IX. Although treatment advances during the last three decades have permitted a near-normal lifestyle and life-span for many individuals with hemophilia, complications of treatment and inability to prevent acute bleeding episodes result in significant morbidity and mortality. Before 1985, more than 80 percent of severe hemophiliacs became infected with HIV. This initiative supports research on gene therapy for hemophilia to eliminate the threat of blood-product transmission of infectious disease.
This program supports 8 grants and will continue through 1999.
R01 HL53665 - Wadie Bahou - State University of New York, Stony Brook, NY
R01 HL53668 - Katherine High - Children's Hospital of Philadelphia, Philadelphia,
PA
R01 HL53670 - Inder Verma - Salk Institute for Biological Studies, La Jolla, CA
R01 HL53672 - Richard Hanson - Case Western Reserve University, Cleveland,
OH
R01 HL5368 - Theodore Friedman - University of California, San Diego, CA
R01 HL53694 - Brian Seed - Massachusetts General Hospital, Boston, M
R01 HL53713 - Kotoku Kurachi - University of Michigan, Ann Arbor, MI
R01 HL53777 - Randal Kaufman - University of Michigan, Ann Arbor, MI
Research in the area of gene therapy for hemophiliacs continues to progress with improvements in gene constructs and vector systems, and with increased understanding of gene delivery systems. Recently two laboratories reported persistent expression of therapeutic levels of human factor IX (hfIX) in mice. One approach was ex vivo, using myoblast-mediated gene transfer of hfIX, with repeat injection of transduced myoblasts. The second approach used recombinant adeno-associated virus vectors, administered by intramuscular injection for muscle tissue expression of hfIX. The reports showed hfIX expression in immunodeficient mice for at least 6-10 months. These studies represent an important advance in gene therapy research for hemophilia B.
The objective of this program is to support basic research on the etiology, mechanisms of pathogenesis and host determinants that are involved in the initiation and progression of interstitial infiltrative diseases in the lung associated with HIV infection. Homing and activation of specific lymphocyte subpopulations will be investigated by using various animal model systems. The interaction among cells involved in lung defenses and the dysregulation of immune mechanisms in the lung provide major themes for the proposed investigations.
This program supports 7 grants and will continue through 1999.
R01 HL53229 - Mark Wewers - Ohio State Univ. Research Foundation, Columbus,
OH
R01 HL53244 - James Demartini - Colorado State University, Ft. Collins, CO
R01 HL53246 - Donald Cohen - University of Kentucky, Lexington, KY
R01 HL53247 - Elizabeth Rich - Case Western Reserve University, Cleveland,
OH
R01 HL53248 - M. Christine Zink - Johns Hopkins University, Baltimore, MD
R29 HL53231 - Homer Twigg - Indiana University, Indianapolis, IN
R29 HL53249 - Jussi Saukkonen - Boston University, Boston, MA
One grantee, who is studying the effect of CD8+ cells in the lung, found that factors elaborated by alveolar macrophages may play a significant role in regulating migration of these lymphocytes to the lung. It has been observed that CD8+ cells from lung washings of HIV-infected patients secrete more monocyte chemotactic protein (MCP-1) than similar cells from uninfected subjects. This is important because MCP-1 inhibits HIV replication through the co-entry factor which is also the MCP-1 receptor. It has also been reported that whereas CD4+ cells of HIV-infected subjects can migrate across unstimulated endothelial cells, CD8+ T cells can only get across endothelial cells pre-activated with TNF-alpha and IFN-gamma . Interestingly, activation of the endothelial cells also increases MCP-1, and the role of this cytokine in transmigration is under investigation. A number of other grantees are examining animal models of HIV-related lung disease; one grantee is studying the effect of a strain of SIV which normally infects macrophages in macaques monkeys. She found that both viral replication and immunosuppression are necessary for the development of pulmonary disease. Another group is studying the lamb model of ovine lentivirus infection and found that the pulmonary infiltrates that result from infection are composed of neutrophils and macrophages, some of which actively produce the virus. The macrophages may well serve as a reservoir of infection within the lung tissue.
The objective of this initiative is to facilitate our understanding of the mechanisms of toxicity of hemoglobin-based oxygen carriers. This program encourages research addressing such fundamental questions as: 1) what are the mechanisms of vasoactivity of hemoglobin solutions? 2) how do protein modifications affect vasoactivity? 3) what are the mechanisms of stimulation of inflammation mediators by hemoglobin-based oxygen carriers? 4) how can this stimulation be prevented? 5) what animal or in vitro models are best used to study toxic effects of oxygen carriers? 6) what are the long-term (metabolic and pharmacologic) effects of oxygen carriers? and 7) what models are best to emonstrate efficacy in terms of oxygen transport to tissue?
An alternative to red blood cells for transfusion has been sought unsuccessfully for over one hundred years. In recent years, the NHLBI and other government agencies have supported research on the development of stable oxygen carriers that do not need to be cross-matched and that can be stored for extended periods of time. During the past decade, awareness of the dangers inherent in transfusion of allogeneic red blood cells has heightened. These include transmission of infectious agents such as HIV, hepatitis viruses and other microorganisms. Consequently, physicians are increasingly reluctant to transfuse their patients and patients are increasingly reluctant to receive blood. Although testing units of blood is becoming more comprehensive and efficient, there is no question that products free of infectious agents which could be used in place of red cells would have wide clinical application. In spite of this promise, studies of hemoglobin-based oxygen carriers have been disappointing as unpredictable toxicities have thwarted development of clinically useful products.
This program supports 7 grants and will continue through 1999.
R01 HL53030 - Ruth Billings - Colorado State University, Ft. Collins, CO
R01 HL53031 - Wilfred Lieberthal - Boston University Medical Center, Boston,
MA
R01 HL53040 - S. Scott Panter - Virginia Medical Center, Richmond, VA
R01 HL53047 - Ann Baldwin - University of Arizona, Tucson, AZ
R01 HL53052 - William Phillips - University of Texas, San Antonio, TX
R01 HL53053 - Thomas Hintze - New York Medical College, New York, NY
R01 HL54138 - Nader Abraham - Rockefeller University, New York, NY
Investigators in the program are evaluating the effects of different classes of hemoglobin-based oxygen carriers (e.g., cross-linked, conjugated, polymerized, lyposome-encapsulated) on various organ systems including the liver, kidney and brain. The effects of these artificial oxygen carriers are many and varied. Hemoglobin preparations have been shown to be neurotoxic in cell cultures of neurons and astrocytes. Lyposome-encapsulated hemoglobin has been shown to cause transient thrombocytopenia in rabbits. A conjugated hemoglobin preparation was shown to rapidly extravasate from intestinal villi of the rat producing mast cell degeneration, tissue edema and epithelial cell detachment. Several oxygen carriers have been shown to be vasoactive causing vasoconstriction in a variety animal models. Studies are ongoing to elucidate the mechanisms of these observed toxicities.