CYL458: Biomaterials

Systemic toxicity and hypersensitivity

Yashveer Singh, PhD
Department of Chemistry

6 April 2015

Systemic toxicity (non-immune)

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

Systemic toxicity (non-immune)

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
BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press

Systemic toxicity due to the immune response

(hypersensitivity)
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
BT Ratner, Biomaterials Science: An Introduction to Materials in Medicine, CRC Press

White blood cells (leukocytes)

The leukocytes are less than
erythrocytes.
These
are
major
component of body defense mechanism
Neutrophils: Most abundant. Kill and
ingest bacteria and fungi
Neutrophils

Lymphocytes:
T
cells
(T
lymphocytes) and natural killer T cells
protect against viral infection. B cells
(B lymphocyes) differentiate into
antibody producing cells

merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html

White blood cells (leukocytes)

Monocytes:
macrophages

It

differentiates

into

Eosinophils: Kill parasites and cancer cells

and responsible for allergic response
Basophils: Allergic responses

merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html

White blood cells and lymphocytes

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
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html

Lymphatic system
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

merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html

Immunity
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
merckmanuals.com/home/blood_disorders/biology_of_blood/components_of_blood.html

Innate vs adaptive immunity

Figure demonstrating key differences between innate and adaptive

immunity (discussed in later slides)
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Innate immunity
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

http://www.biology.arizona.edu/immunology/tutorials/aids/response.html

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Innate immunity

Macrophages and neutrophils reaching the infection site to engulf

the pathogen

http://www.biology.arizona.edu/immunology/tutorials/aids/response.html

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Innate immunity
The antigen is ingested by
dendritic cells, processed, and
presented to T cells

http://www.merckmanuals.com

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Adaptive immunity

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
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Adaptive immunity
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

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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Antibody
There are five major
classes of antibodies:
IgG, IgA, IgD, IgE, and
IgM

Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Antibodies

Murine mAbs produce human anti-mouse antibodies (HAMA) and

therefore engineered antibodies are produced using phage display
library or transgenic mouse
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Antibodies
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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Hybridoma technology
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

Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Adaptive immunity

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

http://www.biology.arizona.edu/immunology/tutorials/aids/response.html

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Adaptive immunity

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 cellmediated immune responses
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Adaptive immunity
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

Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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Adaptive immunity
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)
Crommelin, Pharmaceutical Biotechnology Fundamentals and Applications, Informa

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