Subcutaneous Immunotherapy

SCIT

Effective doses in DB studies

RW (amb a 1)              4-24ug       ? 0.6 & 2.0

Dpt Der p1                  3.25-12ug           0.7

Der f 1                        10ug      

Timothy  Phl p5            15 & 20ug          2 ug

Fel d 1                        11-17ug          .6 & 3.0

Can f 1                        15 ug             .6 & 3.0

Birch Bet v 1                3.28 & 12ug     

Alt a 1                         1.6 ug

Subcutaneous Immunotherapy

SCIT

Evidence for effects on Bronchial Responsiveness

• Impr EARLY response to grass, mite inhalation Bousquet
• Impr LATE bronchial resp to mite inhalation  Van Bever
• Impr nonspecific broncial response to inhaled histamine p cat ITX  Hedlin

• Decreased seasonal rise in BALF eos  (birch)
• Decr nasal infl cells   (mite)
• Decr seasonal rise in nasal basos and eos (grass)
• Decr seasonal rise in activ mast cells (c-kit+) in nasal tissue (grass)

• Incr specific IgG, esp IgG4 and 
• Initial rise then fall in specific IgE

Note: neither change is associated with clinical improvement (epiphenomena??)

Subcutaneous Immunotherapy

SCIT

Evidence for effects on Immunologic Response:

T cell

• Decr ag stim Tcell prolif
• Incr regulatory ag-specific suppressor  Tcells (CD4+CD25+), &  incr IL-10 secr which also increases IgG4 prod) early (1st 70 days)
• Incr TGF B-suppression of Th1 and Th2 cytokine releaseand allergen driven T cell prolif
• Decr expr Th2, incr Th1 expression w allergen stimulation

• Increased IL-12 mRNA (which generates Th1 response)  assoc w decr in LPR ST
• IL-12 + cells correlate positively w IFN-G+ cells  (Th1) and inversely w IL-4+ cells (Th2)

Sublingual Immunotherapy

Evidence for effects on

T cell tolerance and Th2 to Th1 deviation

• 4 weeks:  IL-10 secreting regulatory T cells demonstrate non-allergen specific t cell suppression
• 52 weeks:  regulatory T cells decline, allergen-specific Tcell suppression and IFN-G production enhanced, IL-4 decreased if shift of Th2 to Th1

• Decreases new sensitizations in monosensitized
• Decreased progression to asthma in  pts w only allergic rhinitis

Good evidence w

• mite  at 3.5mg dose and 
• timothy at 20ug  (2/3 of controls progressed vs 1/3 of treated) in elementary aged children   
• odds ratio: untreated about 2.5 times as likely to develop asthma as those treated and persisted at both 3 and 7 years 

• Safety related to specfic IgE epitope which are not involved in clinical response mechanisms
• Efficacy  related to direct action on Tlymphocytes/immune deviation
• Thus, preserving T cell epitopes is relevant to efficacy, reducing/removing IgE epitopes relevant to safety

• Delay absorbtion from admin site and therefore systemic release ie                        ---aluminum adsorption decreases systemic rxns by 90% (avail in ltd  # extracts in US),             --tyrosine adsorption  more ltd in US                --Liposome encapsulation
• Omazilub to decrease total IgE levels
• Alternative routes of administration ie nasal, oral, sublingual, intralymphatic or epicutaneous ie patch test

Omalizumab to decrease total IgE levels:

• Casale:  1/6 reactions c/w placebo in rush protocol, no systemic reactions in weekly build up patients on omalizumab

Sublingual Immunotherapy

Safety 

• Safe, convenient (high incidence of oral reactions in 50% early in course)
• Systemic reactions but no fatal
• Given at home on daily basis
• Less effective than SCIT but
• Demonstrated prevention of new sensitization and progression to asthma
• Demonstrated efficacy after stopping

Sublingual Immunotherapy

Efficacy upsides

• Similar mechanism as SCIT
•  
• +Demonstrated prevention of new sensitization and progression to asthma
• +Demonstrated persistence of efficacy after stopping

BUT :

• Less effective than SCIT (? 50% as effective in first year)
• Untested and ? interference w multiple allergens
• Lack of current approved extracts and billing codes

• Less effective than SCIT (? 50% as effective in first year).  
• Cumulative monthly effective dose about 35X that of monthly SCIT antigen used  ?cost                            
• Untested and ? interference w multiple allergens
• Lack of current approved extracts and billing codes

Subcutaneous Immunotherapy

SCIT

Other approaches to improve safety

• Modify allergens alter IgE epitopes (retain immunogenicity and enable higher, safer dose)                                                          ie allergoids and polymerized extracts                    but T cell effects similarly decreased
• Recombinant technology gives reproducible extract but no advantage in saftety or cost
• Site directed mutagenesis-no advantage
• Peptides- readdressed recently, in Phase 3
• Immune stimulation: adjuvent to react wi TLR to favor Th1 over Th2 response

• Immunoregulatory sequences bind covalently to antigen ie Amb a 2 in Creticos study
• stimulate TLR 9 resulting in IFN G, IL6, 12 and IL18 to create Th1 mileu in naive T cells
• stearically impair access of IgE to antigen without modifying antigen, but allow uptake by Ag presenting cells, TLR stimulation, Th2 to Th1
• Study done with only 6 injections
• Improvement  over 2 seasons despite one season of tx in small n trial, but subsequent trials with large N did not show response