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Module 3 > Induction of mucossal tolerance in AI disease > Flashcards

Induction of mucossal tolerance in AI disease Flashcards

1
Q

What is mucosal tolerance?

A

peripheral immunological tolerance may be induced by the mucosal administration of autoantigens

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2
Q

Why can induction of mucosal tolerance be a double edged sword?

A

can prevent and improve disease but also worsen AI disease

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3
Q

Why is nasal adminsitration more effective then oral administration of autoantigen?

A

disgestive enzymes can destroy the antigen

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4
Q

What suggests that mucosal tolerance depends on the dose of antigen administered?

A

high doses may lead to clonal deletion of anergy whereas lower doses favrou the devleopment of suppressor mechanisms

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5
Q

When has mucosal tolerance been used to suppress AI disease?

A

after nasal administration of soluble peptides that contained defined T cell epitopes, suppression has been documented in EAE; arthritis; EAMG; GN

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6
Q

What is the suppression of AI disease in mucosal tolerance though to be due to?

A

a distinct subset of Treg cells that secrete anti-inflammatory cytokines

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7
Q

What defines the balance between Th1 and Th2 cells?

A

a regulatory subset called Th3 cells - this has been shown to be important in the induction of mucosal tolerance

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8
Q

How do Th3 cells suppress the immune response?

A

release of TGF-b

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9
Q

What other cell type apart from Th3 have been shown to be involved in mucosal tolerance?

A

Tregs

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10
Q

What cytokine do Tregs use to downregulate T cell function?

A

IL-10

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11
Q

What is Goodpasture’s syndrome?

A

rapidly progressive GN with or withou lung haemorrhage defined by circulating and deposited anti-GBM autoantibodies of proven pathogenicity

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12
Q

What is the autoantigen in Goodpastures?

A

NC1 domain of the a3 chain of type IV collagen

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13
Q

What HLA associations does anti-GBM have?

A

strong positive association with HLA DR15 with a negative assocaition with DR7

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14
Q

What are the treatments for Goodpastures?

A

pred; cyclophosphamide and plasma exchange

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15
Q

How has mucosal tolerance been used in Goodpasture’s?

A

oral and nasal administration of glomulerular basement membrane/ recombinant rat z3 (IV) NC1 has prevented the development of EAG

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16
Q

What are the steps in creating an antigen-specific therapy for the treatment of anti-GBM disease?

A

identify an immunodominant T and B cell epitope from a3 (IV) NC1; investigate whether this peptide is nephritogenic; examine the effect of nasal administration in the induction of mucosal tolerance and if effective as treatment in established disease

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17
Q

How was the immunodominant peptide for EAG determined?

A

2 epitopes that goodpasture antivodies recognise; from one of them, different peptides were constructed and rats were immunsed with the 5 different overlapping peptides and looks to see if rat developed disease and use the rat blood to see the antibody and T cell responses to the different peptides

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18
Q

How were the antibody responses to the peptides determined?

A

ELISA plates coated with a3 (IV) NC1 and the different peptides; rat immunised with either a3 or P2 reacted most strongly to a3 (IV) Nc1 plate; P2 plate, rats blood immunised with both a3 and P2 reponded to P2–P2 is the B cell epitope

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19
Q

How were the T cell repsonses to the different peptides detemrined?

A

immunised animals with the different peptides and a3 had their spleen T cells cultured with the 5 peptides and a3 (IV)NC1 and looked at T cell prolfieration. Rate immunised with a3 had highest proliferation in response to a3 and P2; whilst rate immunised with peptide 2 reponded to a3 and P2

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20
Q

What happens if a rat is immunised with P2?

A

it induces EAG

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21
Q

How was the ability of P2 to prevent EAG determined?

A

immunodominant P2 was given nasally to rats at different doses prior to immunisation with a3 and monitored for disease

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22
Q

What was the antibody repsonse of rats given P2 prior to immunisation?

A

the middle dose of 300 reduced circulating antibodies a little; whilst the lower and higher doses had no effect, deposited antibodies were greatly reduced by P2

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23
Q

What was the effect of P2 administration before immunisation on disease severity?

A

reduced on immunofluoresence; proteinuria to the level of negative control; massively redued noumbers of abnormal glomeruli on histolgy; reduced macrophage and scarring in the tissue

24
Q

What was the effect of P2 administration on mucosal tolerance?

A

mice immunised with P2 had much lower T cell prolfieration in repsonse to a3 (IV) NC1 suggesting some tolerance had been induced

25
Q

How was P2 as a treatment tried?

A

peptide 2 was given at different doses 16-18 days after rat immunisation with a3 and disease monitored

26
Q

What was hte effect of using P2 to treat on antibodies?

A

no effect on circulating or deposted antibodies (already estabilshed by day 16- T cell disease by then)

27
Q

What was the effect of P2 as a treatment on the disease severity?

A

there was a dose reponse effect with proteinuria- increased dose had massively reduced proteinuria; reduced abnormal glomeruli; cell infiltration by both T cells and macrophages;

28
Q

What was the effect of P2 in inducing immunological tolerance inestabished disease?

A

T cells from mice immunised with highest dose of P2 showed the same level of T cell proliferation to a3 as the negative control

29
Q

Overall what was the effect of nasally administering P2?

A

prior to immunisation prevented the development of EAG, whilst after onset of disease, ameliorated the development

30
Q

What are the possibilities in the future given the success of P2 in EAG?

A

antigen-specific therapy should be of value in designing new therapeutic stratgies fro patients with anti-GBM and other autoimmune disorders

31
Q

When have trials been done in inducing mucosal tolerance in other diseases?

A

oral myelin in MS; type II colagen in RA; insulin in T1DM- but htese have not demonstrated clinical efficacy

32
Q

What are the potenital reasons why clinical therapies for mucosal tolerance in AI disease not been effecive?

A

have used oral administration- less effective; specific peptides rather than complex antigens may improve efficacy

33
Q

What are the 2 major mechanisms of mucosal tolerance induction?

A

anergy/deletion of antigen-specific T ells and/or selective expansion of cells producing immunosuppressive cytokines

34
Q

What animal models has oral or nasal administration been effective again?

A

EAE; collagen induced arthritis; IDDM; EAMG (myasthenia)

35
Q

How can the effectiveness of mucosal tolerance be improved?

A

conjunction of toleragens with cytokines may enhance suppression

36
Q

What are the benefits of oral/nasal antigen administration over parenteral immunisation?

A

higher efficacy to achieve both mucosal and systemic immunity; minimisation of adverse effects; easy delivery and low costs

37
Q

Why may stimulation of MALT in neonates contrubite to autoimmunity?

A

immunological priming- oral administration of myelin basic protein to neonatal animals enhanced disease expression- immaturity of the immunoregulatory netowrk association with oral toleracne and sensitisation may contribute to pathogenesis of AI disease, this effect decreases at around 4 weeks of life

38
Q

Give an example of how the specific peptide chosen from a protein determines the response ?

A

MBP peptide 21-40 suppressed EAE induced by 71-90 peptide but not delayed hypersensitivity to that peptide, although it did suppress DTH to the whole MBP, there was no suppression seen after administration of 71-90–distinct suppressor determinants exist on MBP ; one amino acid difference meant there was no protection- structure is very important

39
Q

How does the affinity of the peptide to MHC affect the immune response induced?

A

high affinity binding to MHC are more likely to induce tolerance whereas low affinity peptides will allow autoreactive cells to persist in health individuals

40
Q

What does the clustering of autoimmune disases in patients suggest about their aetiology?

A

general inherited perdisposition to autoimmunity that might arise from breakdown of a common mechanism of immunological self-toleracne

41
Q

What is the mechanism by which low doses of orally administered antigen induce regulatory T cells?

A

taken up by mucosa-associated APCs which preferentially induce Tregs

42
Q

What is the process by which high doses of orally adminstered antigen induce anergy ?

A

appear to pass through the gut and enter the systemic circulation and induce clonal deletion/anergy

43
Q

What is the use of bystander suppression in mucosal tolerance?

A

process by which regulatory cells induced by oral antigen secrete antigen-nonspecific cytokines fter being triggered which suppress all immune response –don’t need to know the specific antigen for an organ specific inflammatory disease

44
Q

When has bystander suppression been shown in inducing mucosal toleracne?

A

PLP (proteolipid protein) peptide-induced EAE has been inhibited by feeding MBP; MBP-specific T cells can suppress PLP-induced disease

45
Q

What indicates that self-tolerance is often incomplete?

A

frequency of AI disease and the ability to readily recruit autoreactive T cells from peripheral lymphoid organs

46
Q

Give an exmaple of where dosing can cause problems in mucosal tolerance?

A

oral administration of large amounts of OVA increased disease in a murine model of IDDM after adoptive transfer

47
Q

Why is prevention using mucosal tolerance easier than treatment?

A

in ongoing AI dsiease, most T cells are activated and easy to expand if exposed to the same protein

48
Q

What rat strain are used to induce anti-GBM?

A

WKY strain

49
Q

How have the pathogenic role for anti-GBM antibodies been demonstrated?

A

passive transfer studies- using antibodies from the serum of nephritic mice

50
Q

How have the pathogenic role of T cells in EAG been deomnstrated?

A

they are present in the glomeruli of animals with EAG, proliferate in response to a3(IV) NC1 and transfer disease to naive recipients ; immunotherapy against T cells prevetns or ameliorates disease e.g anti-CD4 and anti-CD8 prevent disease

51
Q

Why has there been a need to identify a specific peptide in anti-GBM?

A

oral administration of GBM antigen and nasal administration of recombinant are effective in preventing disease but not treatment- which is more relevant to patient management

52
Q

Why was an immunodominant peptide thought to be more effective in treating disease than crude preparations of antigen?

A

in other models, nasal administration of synthetic immunodominant peitides has been shown to be more effective in treatment

53
Q

Why may immunodominant peptides be more effective than crude antigen preparations at treating dsiease?

A

peptides containing defined T cell epitopes induce a more specific regulatory immune response than complex antigens

54
Q

Why was higher doses of peptides used in treating EAG than was shown effective in preveting disease?

A

previous studies showed that higher doses of peptides were necessary to treat established disase than prevent

55
Q

What suggestsed that nasal administration of pCol had a preferential inhibitory effect on cell-mediated immunity?

A

there was a significant reduction in number of infiltrating T cell and macrophages despite presence of deposited natibody

Module 3 (33 decks)

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