Lecture 26 GI Mucosal Immunology- Treatment of IBD Flashcards
What are the facets to normal antigen processing in the colon
Epithelial layer Mucous layer Innate immune responses Antigen presenting cells Adaptive immune response Soluble mediators of immunity
Innate immune cells
Granulocyte Mast cell Monocyte Dendritic cell Macrophage NK cell
Adaptive Immune Cells
CD4 T cell
CD8 T cell
B cell
Plasma cell
What is the cytokine milieu and what is it a key determinant of
Environment of the cytokines
T cell differentiation whether it become Th1 or Th2
Name soluble mediators
Cytokines and chemokines
How does Peyer’s patches aid immunity
M cells can sample antigen
APC present to dendritic cells which drain into lymph and give the antigen to a T cell
What do macrophages secrete
Cytokines
What is the function of dendritic cells
Antigen sampling
Present antigen to naive T cells
Where are dendritic cells located
Lamina propria
Peyer’s Patches
What maturation do dendritic cells undergo
Maturation into potent APC by producing cytokines
The interaction between DC and T cells involves what 3 signals
- MHC (DC)/Peptide-TCR (T-cell)
- CD80 (DC)-CD28 (T-cell_
- Cytokine (from dendritic cells)
Name 3 T helper cells
Th1, Th2, Th17
Name 3 T regulatory cells
Th3, Tr1, Treg
How is the gut health maintained
By a balance of T helper cells and T regulatory cells
Pathogenesis of IBD
Poor regulation of T cell response
Treatment strategies for IBD
- 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
Describe multi-cytokine blockade
- Ustekinumab
- Psoriasis, psoriatic arthropathy
- Towards p40 subunit of IL-12 and IL-23
What is Tofacitinib
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)
How can dysbiosis of microbiota be corrected in IBD
- Faecal microbial transplant- restore microbiota
* Used in C. difficile treatment
What is Coeliac disease
• Intolerance to dietary gluten in wheat & similar proteins
What is the genetic susceptibility of coeliacs disease
HLA-DQ2/8 on antigen presenting cells
What are some features of coeliacs disease
- Loss of villi- loss of absorptive capacity
* Increase in intra-epithelial lymphocytes
Name drugs used in Coeliacs disease
Larazotide
ALV003
ImmusanTs Nexvax2 vaccine
Target of Larazotide
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
What is the effect of gluten fragments in enterocytes
induce enterocytes to secrete interleukin-15 which stimulates intraepithelial lymphocytes to attack enterocytes
Target of Nexvax2 vaccine
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
