Contemporary%20Challenges%20to%20the%20Immune%20System

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Contemporary Challenges tothe Immune System
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Infectious Diseases

• More than 400 microbial agents are associated
  with disease
• Licensed vaccines in the United states for 22
  microbial agents
• Vaccines for 34 pathogens have been developed
• Immunological Bioinformatics may be used to
• Identify immunogenic regions in pathogens
• These regions may be used as in rational vaccine
  design
• Which pathogens to focus on? Infectious diseases
  may be ranked based on
• Impact on health
• Dangerousness
• Economic impact

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Human Vaccines against pathogens
Immunological Bioinformatics, The MIT press.
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Deaths from infectious diseases in the world in
2002
www.who.int/entity/whr/2004/annex/topic/en/annex_2
_en.pdf
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(No Transcript)
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HIV/AIDS

• Acquired immunodeficiency syndrome (AIDS)
• Caused by the human immunodeficiency virus (HIV)
• AIDS develops 10 years after infection as the
  concentration of CD4 T cells (the CD count)
  decreases below 20
• WHO tackling HIV/AIDS is the worlds most urgent
  public health challenge
• HAART (highly active antiretroviral therapy )
• Combinations of viral protease inhibitors and
  nucleoside analogues
• Rapid decrease in virus levels
• A slower increase in CD4 T cell counts
• Severe side effects
• Expensive

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HIV

• Retrovirus
• HIV gp120 binds to CD4 on human cells
• Loss of CD4 cells
• Escape mutants
• No vaccine
• No natural immunity reinfection
• Escape from strain specific antibodies
• Broardly neutralizing antibodies are rarely
  produced in patients

Figure by Drs. Louis E. Henderson and Larry
Arthur, http//www.niaid.nih.gov/daids/dtpdb/virta
rg.htm
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Tuberculosis

• Mycobacterium tuberculosis bacteria (Mtb)
• Spread from by airborne droplets
• One third of the worlds population (1.86 billion
  people) is infected
• 10 of the infected develop TB later in life
• 16.2 million people have TB
• Calmette-Guérin (BCG) vaccine used in most
  countries
• Need for improved anti-TB vaccines
• Spread of (multidrug resistant) MDR-TB
• Global burden of the TB epidemic/growing TB/HIV
  coepidemic
• Complicated and costly treatment regimens
• Inadequate diagnostic methods
• The relative ineffectiveness of the current BCG
  vaccines

Figure from http//ucatlas.ucsc.edu/health/tb/tb_
r2000.gif
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Malaria

• Four kinds of malaria parasites can infect
  humans
• Plasmodium falciparum, P. vivax, P. ovale, and P.
  malariae
• 300 to 500 million cases of malaria/year
• More than 1 million people die of malaria each
  year
• Transmitted by bites by an female Anopheles
• Mosquito infected by a previous blood meal

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Malaria life cycle

• The parasites grow and mature in the mosquitos
  gut for a week or more, then travel to the
  mosquitos salivary glands.
• When the mosquito next takes a blood meal, these
  parasites mix with the saliva and are injected
  into the bite
• Once in the blood, the parasites travel to the
  liver and enter liver cells to grow and multiply
• The parasites leave the liver cells and enter red
  blood cells
• Once in the cells, they continue to grow and
  multiply.
• The infected red blood cells rupture, freeing the
  parasites to attack and enter other red blood
  cells
• Toxins released when the red cells burst are what
  cause the typical fever, chills, and flulike
  malaria symptoms
• If a mosquito bites this infected person and
  ingests certain types of malaria parasites
  (gametocytes), the cycle of transmission continues

Figure from http//www.malaria.org/images/lifecyc
le.gif
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Childhood diseases

• Mumps, measles, rubella, chickenpox, whooping
  cough, smallpox, diphtheria, tetanus, and polio
• Successfully been controlled in the developed
  world through vaccines
• Over 1 million still die per year of these
  diseases
• Even in the developed world challenges still
  exist
• Elimination of adverse side effects of vaccines
• Control of childhood diseases in immunologically
  compromised children
• Development of more easily administered,
  "child-friendly" vaccines
• Better control of persisting childhood disease
  threats such as infections caused by rapidly
  evolving organisms like streptococcus and many
  microbes causing pneumococcal infection

In Danish Fåresyge, Mæslinger, Røde hunde,
skoldkopper, kighoste, kopper, difteri,
stivkrampe og polio
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Respiratory infections

• Infections of the respiratory tract is a leading
  cause of illness
• Upper respiratory infections (URIs)
• Seldom have serious or life-threatening
  complications.
• Lower respiratory infections (LRIs) include more
  serious illnesses
• More than 4 million deaths each year
• Common causes (in addition to TB)
• Streptococcus pneumoniae
• Haemophilus influenzae
• Respiratory syncytial virus (RSV)

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Diarrheal Diseases

• More than half of the cases of diarrheal illness
  cannot be ascribed to a particular agent.
• Important pathogens include
• Vibrio cholerae
• Shiga toxinproducing Escherichia coli (STEC)
• Enteropathogenic E. coli (EPEC), Enterotoxigenic
  E. coli (ETEC)
• Helicobacter pylori
• Rotavirus
• Caliciviruses
• Shigella (S. boydii, S. dysenteriae, S. flexneri,
  S. sonnei)
• Salmonella typhi
• Campylobacter

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Recombinant DNA Advisory Committee (RAC)
classification
Risk group 1 (RG1) Agents that are not associated
with disease in healthy adult humans Risk group 2
(RG2) Agents that are associated with human
disease which is rarely serious and for which
preventive or therapeutic interventions are often
available Risk group 3 (RG3) Agents that are
associated with serious or lethal human disease
for which preventive or therapeutic interventions
may be available (high individual risk but low
community risk) Risk group 4 (RG4) Agents that
are likely to cause serious or lethal human
disease for which preventive or therapeutic
interventions are not usually available (high
individual risk and high community risk)
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NIAID/CDC classification

• Category A Diseases/Agents
• Can be easily disseminated or transmitted from
  person to person
• Result in high mortality rates and have the
  potential for major public health impact
• Might cause public panic and social disruption
  and
• Require special action for public health
  preparedness.
• Category B Diseases/Agents (Second highest
  priority agents)
• Are moderately easy to disseminate
• Result in moderate morbidity rates and low
  mortality rates
• Require specific enhancements of CDC's diagnostic
  capacity and enhanced disease surveillance
• Category C Diseases/Agents (Third highest
  priority)
• Emerging pathogens that could be engineered for
  mass dissemination in the future because of
• Availability
• Ease of production and dissemination
• Potential for high morbidity and mortality rates
  and major health impact

http//www.bt.cdc.gov/agent/agentlist-category.asp
catdef
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Pathogenic Viruses

• 1st column (and color of name)DNA Advisory
  Committee guidelines RAC, 2002 which includes
  those biological agents known to infect humans,
  as well as selected animal agents that may pose
  theoretical risks if inoculated into humans. RAC
  divides pathogens intofour classes.Risk group 1
  (RG1). Agents that are not associated with
  disease in healthy adult humansRisk group 2
  (RG2). Agents that are associated with human
  disease which is rarely serious and for which
  preventive or therapeutic interventions are often
  availableRisk group 3 (RG3). Agents that are
  associated with serious or lethal human disease
  for which preventive or therapeutic interventions
  may be available (high individual risk but low
  community risk)Risk group 4 (RG4). Agents that
  are likely to cause serious or lethal human
  disease for which preventive or therapeutic
  interventions are not usually available (high
  individual risk and high community risk)2nd
  columnclassification of the pathogens according
  to the Centers for Disease Control and Prevention
  (CDC) bioterror categories AC, where category A
  pathogens are considered the worst bioterror
  threats3rd columnA letter indicating the type
  of vaccine if one is available (A
  acellular/adsorbet C conjugate I inactivated
  L live P polysaccharide R recombinant S
  staphage lysate T toxoid). Lower case indicates
  that the vaccine is released as an
  investigational new drug (IND)).

Adapted from Immunological Bioinformatics, The
MIT press. Data derived from /www.cbs.dtu.dk/datab
ases/Dodo.
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Pathogenic Bacteria
Adapted from Immunological Bioinformatics, The
MIT press.Data derived from www.cbs.dtu.dk/databa
ses/Dodo.
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Pathogenic Parasites
Adapted from Immunological Bioinformatics, The
MIT press.Data derived from www.cbs.dtu.dk/databa
ses/Dodo.
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Pathogenic Fungi
Adapted from Immunological Bioinformatics, The
MIT press.Data derived from www.cbs.dtu.dk/databa
ses/Dodo.
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BiodefenceTargets
www2.niaid.nih.gov/Biodefense/bandc_priority.htm
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Biodefence targets

• Vaccines have only been made for 14 of the more
  than 123 agents on the CDC/NIAID AC list
• For many of the bacterial agents antibiotic
  treatment is possible, but may be inefficient if
  the agent is inhaled
• Category A agents
• Bacillus anthracis (anthrax)
• Clostridium botulinum toxin (botulism)
• Yersinia pestis (plague)
• Variola major (smallpox)
• Francisella tularensis (tularemia)
• Viral hemorrhagic fevers

http//www.bt.cdc.gov/agent/agentlist-category.asp
catdef
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Antrax

• Even with antibiotic treatment inhalation anthrax
  has 40-75 fatality
• An anthrax vaccine adsorbed (AVA) exists
• There are no data to support the efficacy of AVA
  for pulmonary anthrax in humans
• The protective antigen (PA) of B. anthracis
  induces significant protective immunity against
  inhalation spore challenge in animal models
• Pilot lots of a recombinant PA vaccine are
  produced

In Danish miltbrand
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Smallpox

• Eradicated in 1977
• The mortality from smallpox infections is
  approximately 30
• The vaccine has serious side effects and is
  associated with complications which may be
  life-threatening, especially in persons with an
  impaired immune system
• A modified vaccinia Ankara (MVA) vaccine for
  evaluation in a phase I clinical study is being
  produced by Bavarian Nordic and Acambis

In Danish kopper
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Plague

• Natural epidemics of plague have been primarily
  bubonic plague
• Transmitted by fleas from infected rodents
• Inhalation of aerosolized bacilli can lead to a
  pneumonic plague that can spread through the air
  from person to person
• Untreated has a mortality rate that approaches
  100
• A formalin-killed whole-cell vaccine (USP) was
  available until 1999
• It could prevent bubonic plague but could not
  prevent pneumonic plague
• Candidate vaccines based on the F1 and V antigens
  are in clinical trial

In Danish pest
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Botulism

• Caused by Botulinum toxin
• Characterized by peripheral neuromuscular
  blockade.
• Seven antigenic types (A-G) of the toxin exist
• All seven toxins cause similar clinical
  presentation and disease
• botulinum toxins A, B, and E are responsible for
  the vast majority of foodborne botulism cases in
  the United States.
• The heavy chain is not toxic, and has been shown
  to evoke complete protection against the toxin.
• Sequencing of the C. botulinum Hall strain A
  bacterium genome has been completed

In Danish pølseforgiftning
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Tularemia

• Caused by Francisella tularensis
• If untreated, the disease can lead to respiratory
  failure
• Treatment with antibiotics reduces mortality for
  naturally acquired cases by 2 to 60
• A live attenuated tularemia vaccine has been
  administered under an investigational new drug
  (IND) application to thousands of volunteers
• In vivo studies demonstrate that either CD4 or
  CD8 T cells can mediate resolution of live
  vaccine strain (LVS) infections
• Antibodies appear to contribute little, if
  anything, to protective immunity

In Danish harepest
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(No Transcript)
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Viral hemorrhagic fevers (VHFs)

• Viral hemorrhagic fevers encompass a group of
  similar diseases caused by four types of viruses
• Arenaviruses, associated with Argentine,
  Bolivian, and Venezuelan hemorrhagic fevers,
  Lassa fever, and Sabia virusassociated
  hemorrhagic fever
• Bunyaviruses, including Crimean-Congo hemorrhagic
  fever, Rift Valley fever, and Hantavirus
  infection
• Filoviruses, comprising Ebola and Marburg
  hemorrhagic fevers
• Hemorrhagic flaviviruses, including yellow fever,
  dengue hemorrhagic fever, West Nile virus,
  Kyasanur Forest disease, and Omsk hemorrhagic
  fever
• With very few exceptions (yellow fever), no
  vaccines or proven treatments exist
• Many of the diseases are highly fatal

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Cancer

• One of the three leading causes of death in
  industrialized countries
• Caused by cells which grow progressively without
  any regulation
• Tumor rejection antigens
• No successful treatment based on immune
  responses, except for a few types of cancer (see
  e.g., de Leo 2005).
• Tumors are generally genetically unstable, and
  they can lose their antigens by mutation
• Moreover, some tumors lose expression of a
  particular MHC molecule, totally blocking antigen
  presentation.
• These tumors may become susceptible to a natural
  killer (NK) cellmediated response, but, tumors
  that lose only one or two MHC molecules may avoid
  recognition by NK cells

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Allergy

• Allergic reactions are caused by a special class
  of antibodies called immunoglobulin E (IgE)
  antibodies
• IgE responses are, under normal physiological
  conditions protective, especially in response to
  parasitic worms
• Almost half of the inhabitants of North America
  and Europe have allergies to one or more common
  environmental antigens
• Allergic reactions occur when allergens
  cross-link preexisting IgE bound to the mast
  cells
• Treatment
• Desensitization the aim is to shift the antibody
  response from IgE to IgG
• IgG antibodies can bind to the allergen and thus
  prevent it from causing allergic reactions
• Patients are injected with escalating doses of
  allergen

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Autoimmune diseases

• Infections can trigger autoimmune disease
• Susceptibility to autoimmune disease is
  associated mostly with the MHC genotype
• susceptibility is linked most strongly with MHC
  class II alleles, but in some cases there are
  strong associations with particular MHC class I
  alleles
• For many years immunologists have sought to
  develop methods for preventing and treating
  autoimmune diseases by
• Identifying those self antigens that are the
  target of autoimmune processes
• Using vaccines based on these antigens to revert
  the dangerous immune response to a non harmfull
  one
• All of these attempts entail risk, and require
  exact dosage to get any benefit