1

1911-2011

1

2

LEONARD NOON

E St. Marys London UK.

3

Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;1:1572.

4

Noons original hand-drawn chart.The numbers at the sides denote the resistance of the patient, given in terms of the strength of pollen extract, one drop of which was sufficient to excite a conjunctival reaction. The arrows indicate subcutaneous inoculations of pollen extract, quantities given in units described in the text. Figs.1 and 2 refer to a patient at different periods of treatment; Fig.3 shows the response obtained after about a months treatment in another case; and Fig. 4 the early stages of treatment. The subcutaneous injection was begun with small doses every 3 to 4 days and the dose was increased as the intervals between doses too.It was found out in the early stages of immunization that an overdose could induce a severe attack of hay fever, lasting nearly 24 hours, which was not observed in the later stages. After the inoculations there was an increase in tolerance (Fig.1).

5

ROBERT A. COOKE- .- .- shock .

-1910: -1911: .- ALBERT VANDER VEER : , I.D. tests, >> >> >> test & SCIT, hay fever, >> , >> ,

.-1922: 1 SCIT (Journal of Immunology). COOKE: , , SCIT (- ). COCA: . BROWN: SPT vs ID tests.

6

-1912: o SCHLOSS .-1917: o WODEHOUSE .-1917: o WALKER .-1926: PHILIP LEVINE & ARTHUR COCA (IgE) SCIT .-1927: o VANDER VEER, COOKE & SPAIN hay fever SCIT.

7

1930: FREEMANrush immunotherapy 1,5-2 h 14 h.1932: R. COOKE- ,- - . SCIT.1933: A.STULL & R.COOKE- PNU (Protein Nitrogen Units)- standardization .1934: HARRISON- (alum precipitated extracts).1935: COOKEs team- RooseveltN.Y. USA.- blocking SCIT.

8

-1940: A.STULL, R.COOKE & W.SHERMAN depot -1949: SCIT.-1950: & .

-1935: MARY LOVELESS Cooke. blocking , .-1937: LOUIS TUFT .

MARY LOVELESS

9

1951 - 1970Scit Scit

10

1951:LOWELL & FRANKLIN SCIT (DB Ragweed-SCIT).

1954: MARY LOVELESS - SCIT . -Rush SCIT ( 6 1 ).

1955: (1 ). , . 2000 FDA & .

1957: MARY LOVELESS (adjuvants) .

1957: .

11

-1962: POTTER & BOYCE - .

-1950 1970: : - BURNET: clonal selection theory - - - - .

1967: ISHIZAKA & ISHIZAKA IgE .

& .

12

13

14

15

SCIT

16

SCIT- - (Metzger et al, 1987)- SCIT FEV1>)- / = 4% (Reid , Nelson)

17

- ( IgG -) . (Sobotka, Valentine, Ishizaka, Lichtenstein, Hunt, 1970).

-M , . (Lockley et al, 1982)

- SCIT .

- SCIT

- SCIT

18

1991 - 2010

19

SCIT : 1991 - 2010

20

- SCIT . (Des Roches et al, 1997), (Pajno et al, 2001).

- N SCIT . . (PAT-Study : Moller et al, 2002).

- ~73% & ~57% SCIT. (M.A. Calderon-Cochrane Database Syst Rev, 2007).

- SCIT ( 9,5-14) (Johnstone & Dutton, 1968), (Cools et al, 2000)

1991 - 2010

21

SCIT1991 2010

TH2 TH1 , mRNA INF- & IL-10.(Durham et al, 1996), ( 2001-2004).

- IL-10 (2-4 w) & . , IgG4 (6-12 w).(Francis et al, 2008)

- - , Foxp31CD25+CD3+ - SCIT & & .(Radulovic et al, 2008)

- IgG4 blocking , SCIT.(Frew, 2010).

22

23

24

25

( 100 ?)

26

: - - - &

27

28

- SCIT plus OMALIZUMAB

- TOLL-like Receptors

- Allergoids

- Recombinant Allergens

- Peptides

- Other Routes of Administration

29

SCIT plus OMALIZUMAB

OMALIZUMAB(anti-IgE ) SCIT.

-plan: Omalizumab IgE & FcR1 receptors , . SCIT .

30

SCIT plus OMALIZUMAB

( ): 9 w Omalizumab placebo, 1-day rush placebo . 12 w Omalizumab placebo + maintenance .Omalizumab group: 5 SCIT, & .(T.B.Casale et al.,JACI 117, 2006). ( ): Omalizumab + SCIT(maintenance) - vs- SCIT () Omalizumab group.(J. Kuehr et al, JACI 109, 2002).- : 12w Omalizumab placebo, SCIT ()Omalizumab group: SCIT, , .(M.Massanari et al, JACI 125, 2010).

31

: SCIT plus omalizumab - scit - . :- Omalizumab, SCIT 3-5 ?- ?

32

TOLL-like Receptors (TLR)

= , TH1 regulatory T-cell . .. TLR-4 (.LPSs), TLR-9 - CpGs DNA.

Plan: TLR- SCIT.

33

TOLL-like Receptors (TLR)

POLLINEX QUATTRO (Allergy Therapeutics, West Sussex, U.K.)= glutaraldehyde L-tyrosine TLR-4 monophosphoryl lipid A. - & . . , , . , 3 w.: - SPT. - >> >> IgE. - >> IgG. - ~ 93,5% . - ~ 80% >> - ~ 6,3% . - ( ) ~ 0,5%.

CpG (ISSs) (.. Ragweed). (phase II).

34

ALLERGOIDS

glutaraldehyde formaldehyde , IgE-epitopes T-cell epitopes. , FDA (). - POLLINEX QUATTRO - ALLERGOVIT (Allergopharma KG Reinbek, Germany) - DEPOGOID (Leti Pharma GmbH, Witten, Germany)

( ): - & - IgG1 & IgG4 - (conjunctival provocation testing)

: - ? ( ).

35

RECOMBINANT ALLERGENS ( )

= , , & .

: , , .

/ .

( ): - IgG1 & IgG4, - SPT, - oral allergy syndrome.

( ): - (trimer- recombinant allergens). - (fragments-recombinant allergens).

36

PEPTIDES () T-cell , & .

, 3 .

Allervax Cat Immunologic, Waltham, Mass) , 2 , 230 . . .

Bee Venom Peptide Immunotherapy (5). . .

.

37

& : .

: .

PATCH : .

(ORAL IMMUN.)M : , & .

(ORAL + SUBLINGUAL IMMUNOTHERAPY)K , , , .

38

SLIT ( )

- .- . FDA. (WAO Position Paper 2009).

: - - - - - - - .

39

75 . 25 : , , .

100!

.. ,

40