systemic toxicity and hypersensitivity
DESCRIPTION
biomaterialsTRANSCRIPT
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1 6 April 2015
Systemic toxicity and hypersensitivity Yashveer Singh, PhD
Department of Chemistry
CYL458: Biomaterials
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Systemic effects of biomaterials are due to direct chemical toxicity,
accumulation of products from wear, corrosion or degradation, and
excess inflammatory responses including the production of various
oxygen radicals, generation of vasoactive products and reactions of
immune system
Systemic toxicity is broadly defined as toxicity at some distance from the site of injury
Systemic toxicity is usually dose dependent
BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press 2
Systemic toxicity (non-immune)
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Systemic toxicity (non-immune)
BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press
Organ Systemic responses
Lungs
Kidney
Joints
Liver
Lymphoid
GI tract
Alteration in air exchange and breathing patterns
Alterations in urine excretion, pain
Pain, swelling, loss of function
Alterations in blood chemistry
Swelling , alteration of blood count
Diarrhea, constipation
Following organs give local responses mostly but may
also be involved in systemic responses
Skin
Eyes
Nose
Rashes, swelling, discoloration
Swelling, itching, watery
Itching, running, sneezing
Brain, skeletal system, muscles do not exhibit observable
signs of systemic toxicity
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The immune system protects the body against invading organism or
pathogen. The majority of infection occurs in mucus membranes.
Unusual, excessive, or uncontrolled immune responses are termed
hypersensitivity
Damage result from the release of chemicals normally confined to internal contents of the cell or by overstimulation of inflammatory
response
Immune responses to biomaterial or its degradation/wear products are difficult to predict because it not only depends on the nature,
dose, and location of these released products but also the genetics of
an individual
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Systemic toxicity due to the immune response
(hypersensitivity)
BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press
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The leukocytes are less than erythrocytes. These are major
component of body defense mechanism
Neutrophils: Most abundant. Kill and ingest bacteria and fungi
Lymphocytes: T cells (T lymphocytes) and natural killer T cells
protect against viral infection. B cells
(B lymphocyes) differentiate into
antibody producing cells
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White blood cells (leukocytes)
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html
Neutrophils
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Monocytes: It differentiates into macrophages
Eosinophils: Kill parasites and cancer cells and responsible for allergic response
Basophils: Allergic responses
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White blood cells (leukocytes)
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html
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Interleukin: A cytokine secreted by some white blood cells to signal other white blood cells
Lymphocyte: The white blood cells that differentiates into B cells and T cells and kill infected and cancer cells using killer T cells
T cell (T lymphocyte): Includes helper, killer (cytotoxic), or regulatory T cells
Killer (cytotoxic) T cell: A T cell that recognizes and kills infected or cancer cells
Natural killer cell: A type of white blood cell that recognizes and kills abnormal cell, without having to learn that the cells are
abnormal
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White blood cells and lymphocytes
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html
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The lymphatic system is a network of lymph nodes connected by lymphatic vessels
It transports lymph throughout the body along with foreign substances and dead or damaged
cells into the lymphatic vessels
The substances transported by the lymph pass through at least one lymph node, where foreign
substances are filtered out and destroyed before
fluid is returned to the bloodstream
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Lymphatic system
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html
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Passive immunity: Passive immunity results from the transfer of antibodies from mother to fetus during the pregnancy or the
administration of antibodies (injection) that are otherwise not
produced in your body
Active immunity: When your body acquires immunity due to the exposure to a live pathogen or vaccination
Innate (natural) immunity: Immunity that does not require previous encounter with microorganism/pathogen. Response is quick
Acquired (adaptive) immunity: Previous exposure to a microorganism/pathogen is helpful. Takes time to develop
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Immunity
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html
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Figure demonstrating key differences between innate and adaptive immunity (discussed in later slides)
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Innate vs adaptive immunity
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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Several white blood cells (neutrophils, macrophages) reach the infected area (causes inflammation) and phagocytose the invading
pathogen. Some white blood cells release substances involved in
inflammation and allergic reactions (histamine) or destroy invaders
on their own
The dendritic (DCs) or langerhans cells (LCs) move through out our body and have receptors that allows them to distinguish between
harmless and pathogenic organisms. These cells carry fragments of
pathogen to lymph nodes where they either prevent or stimulate an
adaptive immune response
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Innate immunity
http://www.biology.arizona.edu/immunology/tutorials/aids/response.html
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Macrophages and neutrophils reaching the infection site to engulf the pathogen
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Innate immunity
http://www.biology.arizona.edu/immunology/tutorials/aids/response.html
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The antigen is ingested by dendritic cells, processed, and
presented to T cells
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Innate immunity
http://www.merckmanuals.com
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Pathogen are taken up by antigen presenting cells. The antigen is processed and presented to T helper cells. Two to three distinct
pathways are possible 14
Adaptive immunity
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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The helper T cells can stimulate B cells to produce antibodies. The antibodies will bind to
the selective antigen and immobilize it, thus
preventing infection (detailed figure on the next
slide)
Once B cell has been activated, it also differentiates into memory cells, which ensures
quick response upon next exposure to the same
antigen
The antibody-mediated responses termed as humoral immune response
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Adaptive immunity
http://www.biology.arizona.edu/immunology/tutorials/aids/response.html
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Adaptive immunity
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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There are five major classes of antibodies:
IgG, IgA, IgD, IgE, and
IgM
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Antibody
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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Murine mAbs produce human anti-mouse antibodies (HAMA) and therefore engineered antibodies are produced using phage display
library or transgenic mouse
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Antibodies
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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Antibodies
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Antibodies prevent infection by following mechanisms:
(i) The Fc region of antibodies are identified by phagocytic cells,
like macrophages, which express surface receptors for Fc
(ii) The antibody-antigen complexes activate complement, a system
of proteins, cytolytic to pathogens
(iii) The phagocytic cells, like macrophages, express receptors for
complement factors associated with immune complexes, which
enhances the phaogocytosis
(iv) Antibodies directly bind to the receptor binding sites on the virus
surface, thus preventing the viral entry into the host cell
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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The murine hybridoma technology to produce monoclonal antibodies (mAbs) was
developed by Milstein and Kohler
Involves fusion of antibody producing B cells from spleen with myeloma cells
Product is identified using secondary enzyme labeled with chromogenic substrate
and formation of a colored product
indicates a positive hybridoma
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Hybridoma technology
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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It is possible for pathogens to escape antibody detection and enter cells. Under such situations, the surface of infected cells changes,
which is recognized by T cells. Consequently, cytotoxic T cells kill
infected cells
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Adaptive immunity
http://www.biology.arizona.edu/immunology/tutorials/aids/response.html
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In this process, the cells activate phagocytes and/or antigen-specific T-lymphocytes, and releases cytokines to neutralize infection.
Cytotoxic T cells may also cause cell death by apoptosis
These responses, where antibodies are not involved, are called cell-mediated immune responses
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Adaptive immunity
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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The cell-mediated immunity prevents infection by following
mechanisms:
(i) Cytotoxic T-lymphocytes (CTLs) interact with target cells and
kill them by releasing cytolytic proteins like perforin
(ii) T-cells in delayed type hypersensitivity (TDTH) also kill target
cells as CTLs, but these are aided by helper cells, which activate
macrophages
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Adaptive immunity
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa
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Major Histocompatibility Complex (MHC) Class I MHC: The MHC proteins present antigens to cytotoxic T lymphocytes (CTLs). The T cell receptors (TCRs) recognize peptides
expressed in complex with MHC Class I. For binding to occur, TCRs
must have a structure that allows it to interact with the peptide-MHC
complex and the accessory molecule, CD8, bind to the alpha-3
domain of the MHC Class I
Class II MHC: These MHC proteins are found only on B lymphocytes, macrophages, and cells presenting antigens to T cells,
necessary for communication with B-cells and macrophages. Class II
MHC proteins presenting antigens are detected by a different group
of T cells (T-helper)
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Adaptive immunity
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa