Systemic Toxicity and Hypersensitivity

1 6 April 2015

Systemic toxicity and hypersensitivity Yashveer Singh, PhD

Department of Chemistry

CYL458: Biomaterials

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)

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

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

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

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)


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


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


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


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

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

Macrophages and neutrophils reaching the infection site to engulf the pathogen

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Innate immunity


The antigen is ingested by dendritic cells, processed, and

presented to T cells

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Innate immunity

http://www.merckmanuals.com

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


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


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Adaptive immunity


There are five major classes of antibodies:

IgG, IgA, IgD, IgE, and

IgM

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Antibody


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


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


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


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


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


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


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


Systemic Toxicity and Hypersensitivity

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