This document discusses immunotherapeutic principles and targets for treating autoimmune diseases. It notes that there is no single treatment approach due to complex interactions between pathways and varying efficacy of drugs between conditions. Common treatment approaches include immunosuppressants, removing the triggering antigen or tissue, targeting specific cell types like B-cells, blocking co-stimulatory molecules, targeting inflammatory pathways, and antigen-specific immunotherapy to induce tolerance. New insights into pathways like IFN signatures and potential new targets make treating autoimmunity challenging without a one-size-fits-all solution.

1. AUTOIMMUNITY
and
related Disorders
part 3
Dr Abhirup Chatterjee
MBBS MD(Medicine)
R G Kar MCH

2. Therapeutics in context of
Autoimmune Diseases

3. • Immunotherapeutic principles
• Targets and their uses in practice
• Efficacy and safety profile
• What are new on the horizon?
• Beyond autoimmunity

4. Immunotherapeutic principles

5. SELF-TOLERANCE/TOLERANCE
CENTRAL
NEGATIVE
SELECTION
RECEPTOR
EDITING
PERIPHERAL
COSTIMULATORY
SIGNAL
LACK OF T-
CELL HELP
REGULATORY
T-CELL/ TReg

6. Treating autoimmunity
• 1. Co-stimulatory blockade
• 2. Regulatory T-cell therapy
• 3. Restoring tolerance
• 4. Manipulating inflammatory pathway

8. Why is it not so ‘simple’ ?
• Complex interaction
• Predominant pathways are different
• Varying efficacy of different drugs in different
disease conditions
• Side-effect profile
• Unidentified yet significant pathway/molecule
• In vitro and in vivo disparity
• No “one-for-all” regime
• Don’t know the ‘best-fit’ molecule

11. Why is it not so ‘simple’ ?
• Predominant pathways are different
• Varying efficacy of different drugs in different
disease conditions

12. There is no one ‘right’ path

13. Why is it not so ‘simple’ ?
• Side-effect profile

17. Why is it not so ‘simple’ ?
• Unidentified yet significant pathway/molecule
• In vitro and in vivo disparity
• No “one-for-all” regime
• Don’t know the ‘best-fit’ molecule

19. Let’s be more pragmatic
• Broad spectrum therapy
-Immunosuppressant
-Removal of culprit Ag or tissue: drugs, Sx,
pooled Ig, plasmapheresis, radiation
• Targetted therapy
-Target specific cell type
-Target specific inflammatory pathway
-Target co-stimulatory molecule
-Ag specific immunotherapy

21. Immunosuppressant
• Steroids
• Anti-mitotics
• Other anti-inflammatory drugs

22. Removal of culprit Ag or tissue
• Approach to treat organ-specific AIDs
-Levothyroxine for Hashimoto
-Anti-thyroid in Graves’
-B12 in Pernicious
-Insulin in type 1 DM
-AChE-i in MG
-Thymectomy in MG
-Radioablation in Graves’
-Pancreatic Islet cell implantation in type1 Diabetes
-IFNβ in MS (RRMS type)

23. Target specific cell type
• B-cell Targeted therapy:
-Anti-CD20 Ab: Rituximab (RA, SLE, AAV, ITP, SS,
GPA, EMC, PM/DM), Ocrelizumab, Ofatumumab
-Blys inhibition: Anti-BLys (Belimumab), BLys
receptor signalling blocker
• T-cell Targeted therapy:
-Anti-CD3 and CD4 Ab, Anti-CD52: Alemtuzumab
(CAMPATH-1H)
-Increase Treg activity
- transfer of Treg cells
-Treg-mimicking mechanism: IL10 mediated,
block Th17 mediated response (IL17/23)

24. Target co-stimulatory molecule
• CD28 acts as co-stimulatory receptor and
CD80/86 its ligand;
• Negative co-stimulator receptor: CTLA-4, PD-1,
BTLA
• Effector T-cells up-regulate negative co-
stimulatory receptors at the end of an immune
response, when proliferation is no longer
advantageous, whereas naïve Ts don’t.

27. Co-stimulatory blocker
• Abatacept: Human fusion protein
=[(extracellular portion of CTLA-4) + (Fc
fragment of IgG 1)]
• Approved for RA across the spectrum
especially in MTX non-responders or Anti-TNF
failures

28. Target specific inflammatory pathway
• Tumor Necrosis Factor-α inhibition
• Type I/II Cytokine and JAK/STAT pathway
inhibition
• IL-17/23 inhibition: Ustekinumab
• Cell adhesion and trafficking inhibition:
-S1PR antagonist
-Anti-Integrin
-Vedolizumab

29. Ag specific immunotherapy
• Introduction of tolerogen and induction of
tolerance
• Glatiramer Acetate in MS: to MBP
• BHT-3021 in type 1 DM: to Proinsulin

31. New insights
• IFN signature
• NLRP3
• IL-35
• Semaphorin 3a
• Epigenetics
• Beyond autoimmunity
-cancer: PD-1
-newer therapeutic targets: Alopecia areata
• New light on pathogenesis of diseases: Whipple’s,
Primary CNS vasculitis, few rare syndromes