DCs and tolerance Flashcards
DC stages.
1) Immature DCs: Reside in tissues, they take up pathogens with CLRs + get maturation signal via TLRs (what adjuvants do, 2nd stimulation)
Phagocytosis seen, no T cell activation
Once it sees a pathogen, it goes LN. On the way to the LN, it gets rounder since it doesn’t need to take another pathogen.
2) In LNs, DCs mature. Mature DCs: Doesn’t phagocyte much since it already has an epitope to present.
• MHCs are upregulated to take epitopes to be presented -1st signal
• Co-stimulation molecules upregulated – 2nd signal: CD80-CD86
• Cytokine/chemokine secretion – 3rd signal
can activate naive T cells
Different T cell subsets
CTLs, secrete IFNgamma Th1 secrete IFNgamma - IL2 Th2 secrete IL4 Tfh secrete IL-6 Th17 secrete IL-17 Treg secrete TGFbeta Tregs can suppress both effector T cells and DCs
Tolerance and APCs + tolerance types
When APCs present a self-protein: Either that T cell gets deleted or Tregs increase in thymus.
For B cells, once they get activated for a self-antigen = they either get deleted or undergo receptor rearrangement. = Central tolerance.
As we age, thymus shrinks, so we use 2nd system to induce tolerance = Peripheral tolerance. Either Tregs suppress autoreactive T cells, or once APCs present a self-antigen without any support with cytokines and chemokines = they go Anergy, left alone, can’t give any reaction, or they get deleted.
Allergies - birch pollen
Allergies – Birch pollen example: If you are allergic to hazel, you are allergic to oak (cross reactive) – there’s birch inside those trees = And they get very high response in lungs = IgE, runny nose, watery eye.
Can be diagnosed well, but only treatment is AIT = give allergen low amounts for very long time until they aren’t sensitive anymore for birch pollen.
Overactive immune system attacks foreign but not harmful particles = same with autoimmune diseases
Tolerogenic DCs to suppress autoimmunity + ex vivo production
They decrease costimulatory molecules: = T cells are anergic/deleted/inhibited.
They also have PDL1 to suppress the T cells even more, and they secrete IL-10. These cells can also become Tregs themselves with IL-10, and it leads to suppression of other T cells.
Ex vivo production: isolate monocytes from blood + give factors to make them DCs.
Types of factors that you use to drive toleragenic DCs determine which kind of DC you will get:
If you give dexamethasone, you get a DC that secretes a lot of suppressive cytokines/chemokines, but with rapamycin= you get a DC that hardly secretes any cytokine, only there’s MHC and no costimulation.
Ex vivo produced DC administration :
1) Take blood, get monocytes
2) Generate DCs, give it back + load them w specific Ag.
Clinical trials ex vivo Tolerogenic DCs to suppress autoimmunity + problems
Trials: 1st, type I Diabetes trials: 1 group has their own DCs, 2nd group has DCs with no co-stimulation (Antisense targeting of costimulatory molecules) So they also act as a Treg since they drive anergy.
They loaded citrunilated peptides against RA since the response in RA is against those peptides, and different ways of inducing ex-vivo DCs are used.
Number of patients = too low. Only designed to check that a treatment isn’t super harmful and we won’t get any side effect, since it’s only 1st trial. In next trials they will check whether it works.
Giving toleragenic DCs with no specificity (no Ags) = is a huge problem. They will suppress everything.
Antigens aren’t known so clear for Crohn’s disease or Type I diabetes.
Disadvantages of ex vivo DC preparation:
Personalized: Simply we cannot take blood from 1 patient and prepare DCs for 100 patients, HLA problem.
Laborious
Costly
Might be antigen specific
Other ways to induce toleragenic DCs, tumor associated glycans + SIGLECs
There’s a lot of tumor-associated glycans. They are different than normal, and they bind to a lot of different Lectin receptors on monocytes, macrophages and DCs. And they induce tolerance for cancer to escape immune system.
Let’s look to the TAG that binds to Siglecs on macrophages/monocytes: and recreate this to treat autoimmunity?
SIGLECs are mostly inhibitory, they bind a sugar and phosp. ITIM motif, and it blocks TLR – NFkB signal = inflammation blocked, Tolerogenic.
SIGLEC study - mice + human
Let’s study this sialic acid.
1) Bind sialic acid to an antigen, Ova in this case.
2) Inject it to mice
3) Check whether there’s Ova specific Tregs. = yes
4) IFN gamma and TNF alpha production reduced too. = Treg production suppressed effector T cells, their numbers reduced
Human model to check this:
1) Isolate monocytes from healthy/ RA patients
2) Create moDCs from them
3) Give them antigen + sialic acid
4) Measure cytokines
5) Give naïve T cells too + check Induction of new Tregs and if they can repress effectors
IL-10 secretion / TH1 / Treg
Same thing in mouse model, now they check it for RA.
