National Institute of Allergy and
Infectious Diseases (NIAID) Overview of NIAID Rare Diseases Research
Activities
NIAID research activities on rare diseases are classified into four areas: infectious
diseases, primary immunodeficiency diseases, autoimmune diseases, and allergic diseases.
NIAID's section of this report highlights the Institute's rare diseases advances and
activities.
- Infectious diseases include diseases caused by bacteria, parasites, viruses, and fungi.
Research on rare infectious diseases is aimed at delineating mechanisms of disease
pathogenesis and developing more effective diagnostic, treatment, and prevention
strategies.
- Primary immunodeficiency diseases are hereditary disorders caused by intrinsic defects
in the cells of the immune system and are characterized by unusual susceptibility to
infection. NIAID research is focused on the development of technology to make gene
transfer an effective and curative therapy, and on the identification of gene defects and
immunologic abnormalities that lead to defective function.
- Autoimmune diseases are diseases in which the immune system mistakenly attacks and
damages the body's own cells and tissues. NIAID research is focused on the identification
of mechanisms of pathogenesis and the development of new approaches to prevention and
treatment.
- Allergies are inappropriate or exaggerated reactions of the immune system to substances
that cause no symptoms in the majority of people. NIAID research is focused on the
development of new approaches for the diagnosis, prevention, and treatment of allergic
diseases.
Recent Scientific Advances in Rare Diseases Research
Rare Infectious Diseases
Blastomycosis
Blastomycosis, a systemic fungal infection caused by Blastomyces dermatitidis,
is capable of causing disease in both immunocompetent and immunosuppressed hosts.
Scientists found a genetically proven virulence determinant of B. dermatitidis, a
protein responsible for the ability of invading B. dermatitidis cells to adhere to
host cells (WI-1).
Cryptococcosis
Acquired immune deficiency syndrome (AIDS) patients with cryptococcal meningitis lack
or have a greatly diminished inflammatory response, but still develop increased
cerebrospinal fluid pressure due to mechanisms other than inflammation. Recent studies
have shown that AIDS patients with cryptococcal meningitis experience improved outcome
following mechanical drainage to reduce elevated cerebrospinal fluid pressure.
E. coli O157:H7 and associated hemolytic uremic syndrome (HUS)
E. coli O157:H7 is a life-threatening intestinal pathogen most commonly
associated with consumption of undercooked beef. Infections in humans can lead to bloody
diarrhea and even renal failure in young children and in the elderly. Recent studies
indicate that antibiotics should not be used to treat children presenting with bloody
diarrhea, as antibiotic use could lead to the release of more bacterial toxins and
breakdown of the kidneys, evidenced by bloody urine, and possibly kidney failure from
subsequent HUS. Other researchers determined that intiminO157, an E. coli O157:H7
outer membrane protein, causes attachment of the E. coli to intestinal epithelial
cells.
Haemophilus influenzae type b (Hib)
Hib was the leading cause of bacterial meningitis and other invasive bacterial
disease (meningitis, epiglottitis, septic arthritis, osteomyelitis, and pericarditis)
among children younger than 5 years before the introduction of effective vaccines. New Haemophilus
strains constantly emerge through the process of transformation; strains mutate and
acquire new genetic information. Studies have linked the presence of a 26-base-pair
sequence to several other known transformation genes. A better understanding of the
mechanism of acquisition of new genes by H. influenzae may aid in the development
of better strategies for the suppression of antibiotic-resistant strains and the
identification of new cellular targets for the action of new antimicrobial agents.
Hantavirus Pulmonary Syndrome (HPS)
HPS is a newly emerging, rodent-borne viral disease first identified in the 1993
"Four Corners" epidemic in the southwestern United States. It has a
case-fatality rate of about 50%. New findings suggest immune plasma from survivors might
be a useful approach for treating HPS patients and preventing the development of severe
disease in persons who may have been exposed. Researchers have found an association
between rapid and high-titered neutralizing antibody at medical presentation and increased
survival.
Herpesvirus-associated Neonatal Herpes Simplex Virus (HSV) Infection and Congenital
Cytomegalovirus (CMV)
Neonatal HSV infections can present as a local infection of the skin, eyes, mouth, and
central nervous system, or as a disseminated infection involving multiple organs. The
introduction of antiviral therapy has significantly reduced the mortality rate for
neonatal HSV. Acyclovir has been approved for congenital HSV infection. CMV, another
herpes-associated virus, causes devastating consequences in congenitally infected
children. Most infected infants who survive suffer from profound deafness and/or mental
retardation. Scientists completed a phase III trial of ganciclovir for the treatment of
congenital CMV infections. Symptomatic babies treated with ganciclovir showed improvement
or maintenance of their hearing.
Lyme Disease
Lyme disease, caused by Borrelia burgdorferi, is the most prevalent tick-borne
infectious disease in the United States. A new sensitive and specific laboratory test has
been devised by researchers to diagnose Lyme disease in vaccinated individuals. Other
researchers found that the presence of a soluble CD14 (sCD14) in the blood of patients
with early or late Lyme disease may be an indicator of active infection by B . burgdorferi
. In Lyme disease, damage resulting from autoimmune reactivity to host tissue may add
to the symptoms of infection. Scientists have developed a new method to differentiate
between cell surface components of B. burgdorferi and cell surface components of
the host that may be involved in the autoimmune reaction.
Pertussis
Bordetella pertussis is the primary etiologic agent of pertussis or whooping cough.
Before immunization, pertussis was widespread, with high morbidity and mortality in
infants and young children. Exposure of the host to B. pertussis results in an
increased production of chemicals by human respiratory epithelial cells that cause white
blood cells to be attracted to the area, increased expression of mucin (mucus), altered
mucus consistency, and respiratory cilia paralysis. After effecting these changes, the
organism binds to mucus. Damage to host tissue ensues due to a toxin produced by B.
pertussis . Toxin secretion can be altered by agents that alter membranes. These
discoveries may lead to new strategies for the treatment of whooping cough.
Acute Rheumatic Fever (ARF)
ARF is a disease characterized by inflammatory lesions involving primarily the heart,
joints, subcutaneous tissues, and central nervous system. Cases of ARF follow a group A
streptococcal upper respiratory tract infection, although the exact mechanisms mediating
the development of disease remain speculative. A baboon model has been developed to study
the molecular events necessary for group A streptococci (GAS) to colonize the throat and
to examine aspects of the immune response to GAS in the throat that may be involved in the
development of acute rheumatic fever.
GAS Invasive Disease
GAS can cause invasive disease such as necrotizing fasciitis (flesh-eating bacteria)
and streptococcal toxic shock syndrome. Recently, the crystal three-dimensional structure
of streptococcal pyrogenic exotoxin (SpeB), a major virulence factor of GAS, has been
determined. The three-dimensional structure will provide information that will be useful
for the design of inhibitors with therapeutic potential and vaccine candidates for
prevention of severe invasive disease.
Group B Streptococci (GBS)
GBS cause serious illness in newborns, including sepsis, pneumonia, and meningitis.
Infant and maternal GBS infections may be preventable by maternal immunization. A GBS Type
II capsular polysaccharide-tetanus toxoid (Type II-TT) vaccine in which GBS capsular
polysaccharide was coupled to tetanus toxoid was recently compared to an uncoupled GBS
Type II capsular polysaccharide vaccine. The immune response in the recipients of the
coupled vaccine was significantly higher than that in the recipients of uncoupled vaccine.
This study supports the inclusion of capsular polysaccharide type II coupled to tetanus
toxoid in the formulation of a multivalent GBS vaccine.
Rare Primary Immunodeficiency Diseases
Autoimmune Lymphoproliferative Syndrome (ALPS)
ALPS is a disease in which a genetic defect in programmed cell death, or apoptosis,
leads to the breakdown of lymphocyte regulation, causing a proliferation of lymphocytes
(blood cells critical to immune function). Recent studies have determined that the risk of
becoming ill with ALPS is significantly greater in people who have an abnormality at a
specific location of the fas gene (a gene that codes for a protein that triggers
lymphocytes to die at the completion of their normal life cycle). Individuals with fas gene
mutations are at greater risk for development of B and T cell lymphomas. Researchers have
also identified other mutations involving ALPS.
B Cell Immunodeficiencies
Patients with B cell immunodeficiencies have recurrent, potentially life-threatening
infections due to a lack of mature B cells (which produce antibodies). In an
immunodeficient patient, researchers identified a novel mutation in B cell linker protein
(BLNK), which serves as a "molecular scaffold," bringing together enzymes and
their target molecules in the B cell. Mice with the BLNK mutation were also
immunodeficient.
Chronic Granulomatous Disease (CGD)
CGD is an inherited genetic disorder characterized by a failure of white blood cells
called neutrophils to make oxygen compounds that kill bacteria and fungi. Scientists
recently reported a promising therapeutic approach for individuals with CGD. Patients with
CGD underwent a preparative regimen that causes intense immunosuppression without
destroying the bone marrow, followed by the transplant of immunologically matched sibling
stem cells. This approach provided a cure for a subset of CGD patients with a fully
immunologically matched sibling. In another clinical trial, investigators demonstrated
functional correction of the genetic defect for an X-linked form of CGD in three of five
patients treated with multiple infusions of gene-corrected cells.
Familial Hemophagocytic Lymphohistiocytosis (FHL)
FHL is a rare genetic disorder caused by mutations in at least three genes that results
in uncontrolled activation of the immune system, leading to death in early infancy or
childhood. Researchers demonstrated that a protein called perforin, part of the
cell-destroying apparatus in killer T cells, is missing or inactive in FHL patients.
Job Syndrome
Job syndrome, also known as hyperimmunoglobulin E recurrent infection syndrome (HIE),
is a rare inherited disease characterized by recurrent bacterial infections of the ears
and elevated levels of the antibody immunoglobulin E. Investigators have linked a genetic
defect in HIE patients to chromosome 4.
Severe Combined Immunodeficiency (SCID)
SCID is a rare congenital syndrome response. Some children with SCID have lived for
years in germ-free rooms or "bubbles" necessitated by their unusual
susceptibility to infectious agents that can be life-threatening. A study that may prove
critical to the development of a treatment for SCID involves improving the function of the
thymus by stem cell transplantation. Scientists studied 83 SCID patients who had undergone
bone marrow transplantation to receive stem cells over an 18-year period. T cells that
developed in each patient were identified, characterized, and followed over time with
molecular and cellular markers. The number of T cells reconstituted in the thymus peaked
to near-normal levels 1-2 years after transplantation, with continued thymic function for
up to 14 years.
X-linked Hyper-IgM Syndrome (XHIM)
Individuals with XHIM lack, or have only trace amounts of, several functional classes
of antibodies or immunoglobulins (IgG, IgA, IgE), but have normal or elevated levels of
the antibody IgM, making them highly susceptible to recurrent infections. XHIM is caused
by a defect in the T cell surface molecule CD40 ligand, which binds to the B cell receptor
CD40. Scientists are studying the treatment of patients with XHIM with a synthetic CD40
ligand protein. A second form of XHIM may be caused by a mutation in both CD40 and a
cell-signaling pathway. Patients with this mutation do not produce IL-12 (which is
important in eliciting an immune response to intracellular organisms) upon signaling via
CD40.
Wiskott-Aldrich Syndrome (WAS)
WAS is an inherited blood cell disorder caused by mutation in the WAS protein (WASP).
WAS is characterized by low levels of platelets (cells important for blood clotting),
immune deficiency caused by insufficient number and function of lymphocytes (blood cells
critical to normal immune functioning), and eczema. Researchers have determined that the
level of mutated WASP in platelets and lymphocytes correlates with disease severity.
Rare Autoimmune Diseases
Systemic Lupus Erythematosus (SLE)
SLE is an autoimmune disease characterized by the production of antibodies against
proteins in nuclei of the body's own cells. Antibodies form complexes with nuclear
proteins and become trapped in the kidneys, leading to inflammatory kidney disease.
Scientists showed that C-reactive protein (CRP) promotes clearance of nuclear proteins and
may help prevent lupus-related inflammatory kidney disease. In contrast, estrogen has been
found to enhance the production of antibodies against the body's own cells in lupus in
animal models.
Rare Diseases Research Initiatives
FY 2000-Funded Activities in Infectious Diseases
- NIAID's Mycoses Study Group (MSG) supported four clinical trials examining antifungal
therapy for the opportunistic and endemic mycoses.
- NIAID supported genome sequencing of etiologic agents of rare diseases, including: Rickettsia
typhi (etiologic agent of typhus), Burkholderia mallei (etiologic agent of
glanders), Brucella suis (etiologic agent of brucellosis) , Bacillus anthracis (etiologic
agent of anthrax), Coxiella burnetti (etiologic agent of Q fever), Cryptococcus
neoforman s (etiologic agent of cryptococcosis), E. coli 0157:H7 (etiologic
agent of gastritis and HUS), Ehrlichia phagocytophila (etiologic agent of
ehrlichiosis), Haemophilus ducreyi (etiologic agent of chancroid), Treponema
pallidum (etiologic agent of syphilis), and Streptococcus pyogenes (etiologic
agent of group A streptococci invasive disease) .
- NIAID supported studies on: the identification and characterization of genes that
influence virulence in B. anthracis (etiologic agent of anthrax), factors that
determine host sensitivity or resistance to anthrax lethal factor, genetic factors
involved in the expression of virulence of Yersinia pestis (etiologic agent of
plague), and new animal models to assess the virulence of Rickettsiae (etiologic
agent of Rocky Mountain spotted fever and other spotted fevers).
- NIAID collaborated with the NIH Fogarty International Center (FIC) to support the
"International Training and Research on Emerging Infectious Diseases" program to
address research training needs related to emerging and re-emerging infectious diseases in
developing countries.
- The viral hepatitis program funded a grant for hepatitis A and three grants for
hepatitis D.
- NIAID is supporting phase I/II trials for three different candidate vaccines for human
CMV. These include a glycoprotein subunit, engineered live recombinant viruses, and a
prime-boost strategy using a glycoprotein delivered both as a subunit and in an avian
poxvirus vector (Vaccine and Treatment Evaluation Unit).
- The Collaborative Antiviral Study Group (CASG) conducted phase III studies evaluating
the use of oral acyclovir following the standard of care treatment with intravenous
acyclovir to limit the recurrence of neonatal herpes virus infections of the skin, eyes,
mouth, or central nervous system, and conducted a phase III study evaluating long-term
therapy of herpes simplex encephalitis with oral valacyclovir.
- NIAID supported 46 grants and contracts on Lyme disease. Grants also were awarded to
support research on other vector-borne bacterial infections. These grants support research
on: animal models of disease, microbial physiology, mechanisms of pathogenesis and host
immunity, vectors and disease transmission, therapeutic approaches, and test development.
- A study titled "Study and Treatment of Post Lyme Disease" was completed.
- NIAID supported a phase I clinical trial to evaluate a broadly effective GAS vaccine at
the University of Maryland's Center for Vaccine Development.
- NIAID was the sponsor of a phase I safety and immunogenicity trial utilizing a GBS type
II polysaccharide-tetanus toxoid conjugate vaccine in pregnant women.
- NIAID continues to support research on the epidemiology and basic biology of GBS
disease, along with GBS vaccine research and clinical trials of GBS conjugate vaccines
through a 5-year multidisciplinary contract awarded in late 1997.
- In collaboration with Los Alamos National Laboratories, NIAID has established a
relational database (STD GEN) for pathogens that cause sexually transmitted diseases. The
genomic sequence of HSV1 was incorporated in FY 2000.
- NIAID supported the maintenance of the "World Reference Center for
Arboviruses" and has ongoing contracts to screen possible antiviral compounds for
activity against West Nile virus.
- NIAID participated in the development and support of programs such as The Global
Alliance for Vaccines and Immunization (GAVI) in an effort to protect health and save
lives through the widespread use of safe vaccines.
FY 2000 Newly Issued Initiatives in Infectious Diseases
- Bacteriology and Mycology Study Group (BAMSG) (RFP-AI-01-11): to establish a
collaborative group with expertise to construct and conduct clinical studies addressing
serious fungal and resistant bacterial diseases.
- Animal Models of Human Viral Infections for Experimental Therapies (RFP-AI-01-003): to
evaluate experimental therapies for potential clinical efficacy and toxicity in animal
models of clinically important, emerging, and rare human infections.
- Preparedness Against Illegitimate Use of Bacterial Pathogens (RFA-AI-00-004): to support
the study of virulence determinants, host resistance/susceptibility factors, novel
therapeutics, and novel or improved candidate vaccines against bacterial pathogens
involved in biological warfare, many of which cause rare diseases.
- Challenge Grants: Joint Ventures in Biomedicine and Biotechnology (RFA-AI-00-010): to
promote joint ventures between NIH and the biotechnology, pharmaceutical, and medical
device industries through one-on-one matching of federal dollars by qualified
organizations.
FY 2000-Funded Activities in Immune-mediated Diseases
- NIAID, through a contract with the Immune Deficiency Foundation (IDF), established and
maintains a registry of clinical information on U.S. residents affected by primary
immunodeficiency diseases. For each disease, the registry collects information on
incidence, clinical phenotypes and phenotype/genotype correlations, natural course of the
disease (including complications), effects of therapy, causes of death, and prognosis.
- NIAID, NCI, and the National Institute of Child Health and Human Development (NICHD)
co-funded a research project involving the use of a new screening device to determine if
the occurrence of primary immunodeficiency diseases in large urban Hispanic and African
American populations is underdiagnosed.
- NIAID supported clinical trials and test development for promising tolerance induction
strategies for the treatment of multiple immune-mediated disorders through the Immune
Tolerance Network, an international consortium of more than 70 basic and clinical
investigators from 40 institutions in 9 countries.
- NIAID chairs the Autoimmune Disease Coordinating Committee, an effort to increase
collaboration and to facilitate the development of coordinated research in autoimmune
diseases among the many NIH Institutes, other Federal agencies, and private groups.
- NIAID is sponsoring clinical trials to assess the safety and efficacy of hematopoietic
stem cell transplantation for treating severe autoimmune diseases, along with integrated
studies of underlying mechanisms, through the Clinical Trials Network for Stem Cell
Transplantation for Autoimmune Diseases, established in FY 2000.
- NIAID continued to support research projects awarded in FY 1999 in response to several
trans-NIH initiatives in autoimmunity, including: Environment/Infection/Gene Interaction
in Autoimmunity, Target Organ Damage in Autoimmune Diseases, Pilot Trials on Innovative
Therapies for Rheumatic and Skin Diseases, and Registries for Neonatal Lupus and Juvenile
Rheumatoid Arthritis.
FY 2000 Newly Issued Initiatives in Immune-mediated Diseases
- Asthma and Allergic Diseases Research Centers (RFA-AI-00-012): to support a
multidisciplinary research program focused on studies of immunologic and other mechanisms
underlying human asthma and allergic diseases.
- Innovative Grant on Immune Tolerance (RFA-AI-00-006): to support novel work on the
molecular mechanisms and applications of antigen-specific immune tolerance, which is the
selective and long-term inactivation of the immune responses.
- Hyperaccelerated AwardMechanisms in Immunomodulation Trials (RFA-AI-00-005): to
support mechanistic research studies in clinical trials of interventions that enhance
immune function for immune system-mediated diseases.
- Cooperative Study Group for Autoimmune Disease Prevention (RFA-AI-00-016): to support a
collaborative network of investigators focused on the development of interventions to
prevent autoimmune diseases.
FY 2000 Cooperative Research and Development Agreements (CRADAs)
In FY 2000, NIAID investigators entered into six CRADAs related to rare diseases.
CRADAs funded the production and evaluation of human antiherpes simplex virus monoclonal
antibody as a therapeutic tool for treatment of neonatal HSV, stem cell gene therapy
systems for CGD, the adoptive transfer of T-cell clones for treatment of immunologically
mediated and infectious diseases, the development of a hepatitis A vaccine, and an
acellular pertussis vaccine clinical trial.
Rare Disease-Related Program Workshops, Symposia, and Meetings
- In an effort to stimulate research and research collaborations on rare diseases, NIAID
and the Office of Rare Diseases (ORD) co-sponsored the workshop, "Protocol
Development for Autologous Stem Cell Transplantation (SCT) in Pediatric Rheumatic
Disease."
- NIAID, in collaboration with other NIH Institutes, the Jeffery Modell Foundation, and
the IDF, sponsored a March 2000 symposium titled, "Advances in the Diagnosis and
Treatment of Primary Immunodeficiency Diseases: Risk of Cancer," focusing on advances
in biomedical research that led to new insights into the diagnosis and treatment of
primary immunodeficiency diseases and on the etiology of cancer in primary immunodeficient
patients.
- The June 2000 NIH Lyme Disease Coordinating Committee meeting of focused on several
NIH-supported clinical studies on Lyme disease.
- The NIAID-industry "Summit on Development of Infectious Disease Therapeutics"
was held September 26-27, 2000. Issues of NIAID and industry collaboration in the
development of therapeutics for addressing public health priorities in infectious disease
were discussed.
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