6th Five Year Report
Selected 30-Year Accomplishments

Acquired Immunodeficiency Syndrome Panels

• Discovery that the in situ polymerase chain reaction (PCR) and other single cell techniques have revealed large numbers of infected CD4+ lymphocytes and monocyte/macrophages in lymphoid tissues. Most of these cells are latently infected, which provides a mechanism for HIV not only to elude host defenses but also to productively infect those cells that spread infection and contribute to immune depletion
  
  
• Identification of two ancestral lineages for Japanese strains from phylogenetic studies of HTLV-I/STLV. One probably came to the Americas in paleolithic times, suggesting interspecies transmission in the origins of HTLV-I.
  
  
• An analysis by the Joint Panels of epidemics in Guam, Hong Kong, India, Indonesia, Malaysia, the Marshall Islands, Micronesia, Papua New Guinea, the Philippines, the Republic of Korea, Samoa, and Thailand to monitor the pattern of the Acquired Immunodeficiency Syndrome (AIDS) pandemic, predicts future epidemic trends elsewhere in the region, and identifies research opportunities in Japan and elsewhere in Asia and the Pacific rim countries.
  

Cholera and Related Diarrheal Diseases Panels

• Demonstration that glucose-electrolyte fluids administered orally (oral rehydration therapy or ORT) can reduce mortality associated with cholera to less than 1 percent even in refugee populations in impoverished rural areas
  
  
• Characterization of cholera toxin, its immunogenicity and adjuvanticity, and genetics leading to novel practical approaches to the development of effective vaccines; development and field testing of an oral whole cell/B subunit vaccine that provided significant protection for 3 years in rural Bangladesh; current field testing of a genetically-engineered live oral vaccine in Indonesia; development of a model for government-industry cooperation for production and testing of new, genetically-engineered oral vaccines
  
  
• Recognition and control of new cholera outbreaks in South and Central America, Asia, and Africa; demonstration of effectiveness of whole cell/B subunit vaccine in preventing cholera in exposed populations from Peru in 1993-1995
  
  
• Demonstration that cholera toxin and the nearly identical E. coli heat labile toxin (LT) uniquely and permanently activate the ubiquitous cell signal adenylate cyclase in gut epithelial cells and thereby cause massive intestinal fluid loss; development of new assays for enterotoxins, a greater understanding of anti-secretory drugs, and insight into other disorders of fluid transport, including cystic fibrosis
  
  
• Demonstration that E. coli heat stable toxin (STa) activates guanylate cyclase, a key endogenous mediator of transcellular fluid and electrolyte movement.
  

Environmental Mutagenesis and Carcinogenesis Panels

• Characterization and identification of genes susceptible to certain forms of cancer; particularly BRCA1, the breast cancer susceptibility gene, and KAII, a prostate tumor suppressor gene. The identification of such genes may lead to early prevention/intervention strategies
  
  
• Identification and characterization of naturally occurring carcinogens and application of molecular biology techniques to assess the biological relevance of exposure to a variety of mutagens and carcinogens; this has greatly increased the sensitivity of human epidemiology studies
  
  
• Development and application of new animal models and short-term tests; this has resulted in better characterization of carcinogens, mutagens, and tumor promoters in the general environment and dietary constituents.
  

Hepatitis Panels

• Identification, cloning, and sequencing the genome of at least five human hepatitis viruses
  
  
• Discovery of hepatitis B surface antigen (HBsAg) leading to the development of sensitive diagnostic tests for screening blood and blood products for hepatitis A, B, C, and D
  
  
• Development of first and second generation hepatitis B virus vaccines and initial efforts towards universal immunization against hepatitis B
  
  
• Licensing and use of alpha interferon to treat chronic hepatitis B, C, and even D virus infections.
  

Immunology Boards

• Discovery and characterization of the function of new cytokines that affect B lymphocyte differentiation, activate genes selectively, and induce immunoglobulin isotype expression
  
  
• Major advances in understanding distinct signalling pathways in lymphocytes and identifying those components that transduce and transmit such signals during the course of immune responses
  
  
• Major advances in understanding antigen processing pathways, how peptide epitopes interact with class I and class II MHC molecules, and how T cells are activated via T-cell receptors
  
  
• Recognition of the role of T-cell anergy in unresponsiveness, the involvement of two events in T-cell activation, and the role of co-stimulatory molecules (e.g., CD28) in this process.
  

Leprosy Panels

• Major contributions to the dramatic decline in the estimated number of cases of leprosy from about 20 million 30 years ago to 2.5 million today
  
  
• Development of innovative approaches to alleviate nerve damage
  
  
• Sequencing of over 60 percent of the Mycobacterium leprae genome
  
  
• Complete characterization of the majority of the Mycobacterium leprae protein and carbohydrate antigens
  
  
• Characterization of the major immunological correlates of protective immunity and immunopathogenesis.
  

Malnutrition Panels

• Demonstration that the use of vitamin C and the production of epinephrine are increased by stress
  
  
• Establishment of the role of vitamin A, iron, and calcium deficiencies in the prevalence of malnutrition in Southeast Asia
  
  
• Demonstration that obesity, with accumulation of central abdominal visceral fat, is associated with insulin resistance, increased post-heparin plasma hepatic-lipase activity, and mild dyslipidemia.
  

Parasitic Diseases Panels

• Demonstration of the role of cytokines in protective immunity and disease progression during parasitic infections
  
  
• Demonstration of the role of insect saliva in potentiating the transmission of parasites by insect vectors
  
  
• Identification of defined recombinant and/or synthetic antigens that induce protective immunity against malaria, schistosomiasis, and filariasis in preclinical studies.
  

Tuberculosis Panels

• Dissection of the role of T-cell populations and cytokines in protective immunity, granuloma formation, and immunopathogenesis
  
  
• Identification of mycobacterial targets of the host immune response
  
  
• Development of genetic systems for studying mycobacteria
  
  
• Characterization of the genetic basis for drug resistance in Mycobacterium tuberculosis including isoniazid and rifampin resistance.
  

Viral Diseases Panels

• Development of an improved rabies vaccine
  
  
• Elucidation of the pathogenesis and natural history of hemorrhagic fever viruses
  
  
• Comprehensive expansion of knowledge of viral gastroenteritis that resulted in vaccine development and testing
  
  
• Incorporation of molecular biological methods to better understand the evolution and emergence of arthropod borne viral infections.
  

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