Lecture 26 GI Mucosal Immunology- Treatment of IBD

Question 1

What are the facets to normal antigen processing in the colon

Answer 1

Epithelial layer
Mucous layer
Innate immune responses
Antigen presenting cells
Adaptive immune response
Soluble mediators of immunity

Question 2

Innate immune cells

Answer 2

Granulocyte
Mast cell
Monocyte
Dendritic cell
Macrophage
NK cell

Question 3

Adaptive Immune Cells

Answer 3

CD4 T cell
CD8 T cell
B cell
Plasma cell

Question 4

What is the cytokine milieu and what is it a key determinant of

Answer 4

Environment of the cytokines

T cell differentiation whether it become Th1 or Th2

Question 5

Name soluble mediators

Answer 5

Cytokines and chemokines

Question 6

How does Peyer’s patches aid immunity

Answer 6

M cells can sample antigen

APC present to dendritic cells which drain into lymph and give the antigen to a T cell

Question 7

What do macrophages secrete

Answer 7

Cytokines

Question 8

What is the function of dendritic cells

Answer 8

Antigen sampling

Present antigen to naive T cells

Question 9

Where are dendritic cells located

Answer 9

Lamina propria

Peyer’s Patches

Question 10

What maturation do dendritic cells undergo

Answer 10

Maturation into potent APC by producing cytokines

Question 11

The interaction between DC and T cells involves what 3 signals

Answer 11

1. MHC (DC)/Peptide-TCR (T-cell)
2. CD80 (DC)-CD28 (T-cell_
3. Cytokine (from dendritic cells)

Question 12

Name 3 T helper cells

Answer 12

Th1, Th2, Th17

Question 13

Name 3 T regulatory cells

Answer 13

Th3, Tr1, Treg

Question 14

How is the gut health maintained

Answer 14

By a balance of T helper cells and T regulatory cells

Question 15

Pathogenesis of IBD

Answer 15

Poor regulation of T cell response

Question 16

Treatment strategies for IBD

Answer 16

• Target lymphocytes directly- inhibit proliferation and unable exert exaggerated response
• Target single cytokines- these drive the activation of T cells and IBD TNFs (anti-TNF are antibodies that inhibit pro-inflammatory response)- Adalimumab (less immunogenic)
• Target migration of immune cells to GI mucosa
• Target multiple cytokines
• Target cytokine intracellular signalling pathways
• Modulation of microbiota

Question 17

Describe multi-cytokine blockade

Answer 17

• Ustekinumab
• Psoriasis, psoriatic arthropathy
• Towards p40 subunit of IL-12 and IL-23

Question 18

What is Tofacitinib

Answer 18

Multi-cytokine blocking
• Inhibition of IL-2, IL-7, IL-9, IL-12, IL-15, IL-21, IFN, IL-6, IL-12 and IL-23
• Inhibition of JAK pathway (1&3)

Question 19

How can dysbiosis of microbiota be corrected in IBD

Answer 19

• Faecal microbial transplant- restore microbiota

* Used in C. difficile treatment

Question 20

What is Coeliac disease

Answer 20

• Intolerance to dietary gluten in wheat & similar proteins

Question 21

What is the genetic susceptibility of coeliacs disease

Answer 21

HLA-DQ2/8 on antigen presenting cells

Question 22

What are some features of coeliacs disease

Answer 22

• Loss of villi- loss of absorptive capacity

* Increase in intra-epithelial lymphocytes

Question 23

Name drugs used in Coeliacs disease

Answer 23

Larazotide
ALV003
ImmusanTs Nexvax2 vaccine

Question 24

Target of Larazotide

Answer 24

Stops gluten fragments from reaching the immune system by preventing the protein zonulin binding to target receptors in enterocytes that instruct the cells to loosen up tight junctions

Question 25

What is the effect of gluten fragments in enterocytes

Answer 25

induce enterocytes to secrete interleukin-15 which stimulates intraepithelial lymphocytes to attack enterocytes

Question 26

Target of Nexvax2 vaccine

Answer 26

exposes the immune system to selected fragments of gluten with the aim of inducing T cells to tolerate, rather than react to gluten
• When the modified gluten is presented to helper T cells they are activated, releasing cytokines and chemokines that induce further immune responses