Lecture 3 - immunotoxicity

Question 1

Immunotoxicology

Answer 1

The study of adverse health effects that may result from the interaction of xenobiotics (chemicals) with the immune system

Answer 2

Reduce activity of the immune system
General Immunotoxicity
Carcinogenicity and immunosuppression

Answer 3

Increase activity of the immune system
Immunostimulation eg cytokine storm
Dermal sensitisation
Adverse (systemic) drug reactions
Adverse effects on implanatation/pregnancy
Developmental immunotoxicity

Question 4

Immunotoxicity - immunosuppression

Answer 4

‘Compromised immune function resulting from exposure to xenobiotics’

Direct – interaction of chemicals or drugs with one or more component of the immune system

Indirect – resulting from toxic effects in other organ or physiological systems

Question 5

Innate immunity

Answer 5

• Physical barriers
• Antimicrobial and pro-inflammatory factors
• Phagocytes and natural killer cells
• Inflammation/fever

Question 6

Adaptive immune function

Answer 6

A dedicated system of tissues, cells and molecules that act
in concert to provide specific immune responses

• Memory
• Specificity
• Discrimination between “self” and “non-self”

Question 7

Lymphocytes

Answer 7

Cellular vectors of adaptive immunity

• Specific
• Distinguish between self and non-self
• Provide immunological memory

Selective clonal expansion provides for immunological memory and differentiated effector cells for antigen elimination

Question 8

Antibodies

Answer 8

• neutralization of toxins
• extracellular lysis of bacteria (with complement)
• facilitates internalization for intracellular killing by phagocytes
  (neutrophils and macrophages)
• expulsion of parasites via inflammatory reactions
• passive immunity by transplacental transfer

Question 9

Bruton’s disease

Answer 9

X-linked hypogammaglobinaemia

Absence of circulating B lymphocytes/plasma cells

Reduced or absent immunoglobulins

Failure to clear pyogenic bacteria
Staphylococci, Streptococci, Hemophilus

Opsonisation essential for neutrophil phagocytosis

Recurrent respiratory/middle ear/skin infections

Question 10

T lymphocytes

Answer 10

kill virus-infected cells

resistance against intracellular pathogens

activate macrophages

help antibody responses

immunoregulatory function

Cytokine production
enhanced intracellular killing of
facultative intracellular bacteria
help antibody responses
help cytotoxic T cells

Cytotoxic T lymphocytes
lysis of virally infected host cells

Question 11

SCID

Answer 11

Severe combined immunodeficiency syndrome

Failure to thrive
Viral gastroenteritis
Viral chest infection
Parasitic chest infection
Bacterial septicaemia
Fungal urinary infection

Question 12

AIDS

Answer 12

Acquired immunodeficiency syndrome

Question 13

Immunotoxicity testing

Answer 13

• General indications:
• Haematology (eg lymphocyte subsets)
• Serum immunoglobulins
• Increased incidence infection/tumours
• Lymphoid organ weights
• Histopathology – spleen, thymus, lymph nodes
  bone marrow
• Functional assays
• Host resistance assays

Question 14

Histopathology

Answer 14

altered architecture, especially changes in the ratio
of cortex to medulla, and/or altered cellularity

the presence of lymphocyte degeneration or
necrosis and changes in the number of tingible
body macrophages

the presence of germinal centres

Question 15

Immune function testing

Answer 15

Natural/innate immunity:
* NK cell function
* Phagocyte functions

Cell-mediated immunity:
* Mitogen-induced T lymphocyte proliferation

• Phenotypic (flow cytometric) analysis of lymphocyte populations

Humoral immunity:
* T cell dependent antibody responses
(SRBC/KLH)

Question 16

Host resistant assays

Answer 16

Viral infections:

Herpes cell-mediated immunity

Bacterial infections:

Listeria monocytogenes cell-mediated immunity and macrophage function
Streptococcus pneumoniae humoral immunity and complement

Parasite infections:

Trichinella spiralis cell-mediated immunity
Plasmodium yoelii humoral immunity

Transplantable tumours:

B16F10 melanoma cells cell-mediated immunity/NK cell function

Question 17

Testing immune function

Answer 17

age
gender/endocrine function
infection
nutritional status
stress
exercise

Question 18

Preclinical testing

Answer 18

Co-stimulatory molecule
Anti-CD28 antibodies
conventional
superagonist (TGN)

In rodents superagonists activate Tregs (immunosuppressive)
no cytokine storm due to very efficient Treg activation

Preclinical model – cynomolgus macaque
100% homology with human CD28 molecule/binding affinity
but CD28 expression pattern on Tcells different
CD4 effector memory cells key cell type in humans

Cytokine storm – depends which cells activated

	accessory cells : IL-1β, IL-6, and TNFα 
	CD3 cells: IL‐2, TNFα, and IFN‐γ
	effector memory CD4 cells : IL-2/IFN-γ

	plus many others possible

Question 19

Immune stimulation

Answer 19

immune activation
cytokine release
ligand receptor interactions

Answer 20

• Classical immunotoxicity - immunosuppression