immunomodulatori: come agiscono? - sipps · clinical evaluation and changes in ciliary clearance...

Immunomodulatori: come agiscono?

Alessandro Fiocchi Caserta, 14 settembre 2012

Educational objectives

At the end of this lecture, participants will be able to:

Understand the rationale behind the use of BRMs in prevention and treatment of RRI

Identify the new avenues of research in the fieldIdentify the new avenues of research in the field

Assess the impact of a BRMs in healthy, socialised children

Conflict of interest

Speakers’ Bureau: none

Advisory boards: ALK-Abellò, Pierre Fabre, Stallergènes Italy

Currently sponsored research: MSD, GSK, Pierre Fabre, Paul Ehrlich Institute, Roxall.

This lecture is sponsored by Valeas

Se il bambino si ammala troppo spesso... infezioni catarrali ricorrenti

A parte i discorsi su ambiente sano ed alimentazione sana, si cercherà di evitare i contagi diretti e di abituare il bambino a frequenti lavaggi delle mani .

Comunque, non servono assolutamente i molti vaccini per bocca o immunomodulatori , che impropriamente sono considerati ricostituenti. I

benefici, rispetto ai costi, sono molto limitati; resta sempre aperto il problema della "medicalizzazione" di una situazione non grave e quindi accettabile da parte del bambino e dei suoi genitori. Meglio accettare una infezione benigna in parte del bambino e dei suoi genitori. Meglio accettare una infezione benigna in più piuttosto che sottoporre il bambino a cure costose e di limitata importanza.

[….] non è nemmeno scientifico. Infatti recenti ricerche affermano che, se eliminiamo queste "piccole" malattie, possiamo registrare un aumento di

allergie (asma, eczema, riniti allergiche,…), per deviazione nella maturazione dei linfociti, nostre cellule di difesa. Le reazioni del nostro organismo a

queste malattie infettive sono utili, perché matura no il nostro sistema immunitario di difesa .

http://www.archivio.vivoscuola.it/genitori/famiglia/infezioni.asp

.

1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?

2. I bambini a rischio2. I bambini a rischio

3.3. I BRM I BRM possonopossono agireagire sull’immunitàsull’immunità innatainnata

4. I BRM 4. I BRM possonopossono agireagire sull’immunitàsull’immunità adattivaadattiva

5. I BRM 5. I BRM possonopossono agireagire sull’immunitàsull’immunità naturalenaturale

6. 6. ConcludoConcludo

7. Post7. Post--concludoconcludo

Che carico rappresentano per la società leinfezioni respiratorie acute?

Sono responsabili di: 20% di tutte le visite mediche 30% dei giorni persi dal lavoro

75% delle prescrizioni di antibiotici

Quanti episodi all’anno?

0

2

4

6

8

0-1 1-4 5-9 10-19

età

Calcolato su una popolazione rurale che non frequenta

asilo

Del Rio- Navarro N. Immunostimulants for preventing respiratory tractinfection in children. Cochrane Database Syst Rev. 2011;(4):CD004974.

6

4

Num

ber

epis

oeds

/per

son/

year

# respiratory infections/year by age class

2

Num

ber

epis

oeds

/per

son/

year

età [anni]

<1 50-5940-4930-3925-2920-2415-1910-145-93-4 ≥601-2

Heikkinen T, Järvinen A. The common cold. Lancet. 2003; 361:51-9

World-wide distribution of child deaths from ARI

Williams BG. Estimates of world-wide distribution of child deaths from acute respiratory infections. Lancet Infect Dis 2002;2:25-32

.


2. I bambini a rischio

33.. I BRM I BRM possonopossono agireagire sull’immunitàsull’immunità innatainnata





Some children as a group show high morbidity

• 41 school-age children with RRTIs [antibiotics] as preschoolers (a)

vs.• 29 children (same age and socio-economic background)

whithout RRTIs as preschoolers (b)

Two-year follow-up:

• RTI episodes a>b (p < 0.01)• RTI duration a>b (p < 0.01)

Soderstrom M Respiratory tract infections in children with recurrent episodes as preschoolers. Acta Paediatr Scand. 1991;80:688-95

Certain children constitute a group with high morbidity

Annual incidence of bacterial RTI:

Age Group a Group b P

2 yrs 6.2 1.4 < 0.001

7 yrs 3.1 1.2 < 0.01

� Children with high morbidity are susceptible to RTIsand other illnesses over a long period of years

7 yrs 3.1 1.2 < 0.01

8 yrs 2.4 0.8 < 0.05

Soderstrom M Respiratory tract infections in children with recurrent episodes as preschoolers. Acta Paediatr Scand. 1991;80:688-95

Recurrent respiratory infections can be linked to minor immune defects

IgG2 subclass deficiency � pneumonia, sinusitis, invasive pneumococcal disease

IgA deficiency � pneumonia, otitis, diarrhoea

G2m(n) allotype of IgG2 � susceptibility to encapsulated bacteria

Fc receptor IIa: H131 high affinity, FcRIIa-R131 low affinity for IgG2

Heterozygotic C2 deficiency in 1%–1.5% of the general population

Homozygous deficiency of C4A or C4B in 3% of the population

Mannose-binding lectin (MBL2) activates the complement system

Bossuyt X. Coexistence of (partial) immune defects and risk of recurrent respiratoryinfections. Clin Chem. 2007;53:124-30

.



3. I BRM possono agire sull’immunità innata





TTTTTT

Uninvolved

Th2Th2Th2Th0Th0Th0 IL-10IL-10IL-13

IL-4

IL-5

IL-13

IL-4

IL-5

YTh0Th0Th0

Th1Th1Th1IL-12IL-12

IFN-

IL-4IL-4

remodeling

remodeling

MCMC

Y

Y

Y

TTTTTT

IDECIDEC

IFN-γγγγIL-11

IFN-γγγγIL-11

Y

YTTT TTT TTT YY Y

Y

TTT Y

Y

Y

remodeling

remodeling

McAleer JP. Educating CD4 T cells with vaccine adjuvants: lessons from LPS. Trends Immunol. 2010;31:429-35

Human Toll - like receptors and their ligands.

Peptidoglycan (G+)Lipoprotein

GPI (Trypanosoma cruzi)Zymosan (Yeast)

Mycobacterial lipopeptidesMeasles and CMV proteins dsRNA

LPS (G-)LPS (G+)

Lipoteichoic acids (G+)RSV F protein ssRNA

UnmethylatedCpG DNA

Uropathogenic

bacteriaFlagellin

Courtesy of Lorenzo Moretta

TLR 6 TLR 2 TLR 1 TLR 4

CD14 TLR 3 TLR 5 TLR 9

MD-2TLR 7 TLR 8 TLR 11

Different cell types of the innate immune system can modulate NK-cell responses upon interaction with different microbial

products

Ribomunyl is a potent antiviralToll-like receptor 7/8 agonist.

Ribomunyl has been proposed to activate innate immunity, but the contribution of its RNA content as well as its antiviral

potential has not been studied.

Peripheral blood mononuclear cells (PBMC) from healthy donors & from adenoids incubated with Ribomunyl

- itself - + poly-l-arginine or protamine

⇒ induction of cytokines quantified by ELISA.

Herberhold S. Delivery with polycations extends the immunostimulant Ribomunyl into a potentantiviral Toll-like receptor 7/8 agonist. Antivir Ther. 2011;16:751-8

Ribomunyl is a potent antiviralToll-like receptor 7/8 agonist.

Ribomunyl + either poly-l-arginine or protamine

⇑ interferon-α (P<0.01) in PBMC

⇑ IL-12 (P<0.01) in PBMC⇑ IL-12 (P<0.01) in PBMC

= TNF-α and IL-6

The RNA in Ribomunyl acts as an agonist of TLR7 and TLR8.

Herberhold S. Delivery with polycations extends the immunostimulant Ribomunyl into a potentantiviral Toll-like receptor 7/8 agonist. Antivir Ther. 2011;16:751-8

.




4. I BRM possono agire sull’immunità adattiva




Absence of CD30 leads to reduced airway inflammation in OVA-immunized mice.

Polte T. Direct evidence for a critical role of CD30 in the development of allergic asthma. J Allergy Clin Immunol. 2006;118:942-8

Absence of CD30 leads to reduced airway inflammation and mucus production in OVA-

immunized mice.

Polte T. Direct evidence for a critical role of CD30 in the development of allergic asthma. J Allergy Clin Immunol. 2006;118:942-8

OH+

N

S

=S

N

Pidotimod

ONH

C

O

OHH

N

COOH

N

H

C

O COOH

N

L-Piroglutammic acid

L-Tiazolidin-4-Carbossilic acid

Pidotimod

A synthetic dipeptide with with biological & immunological activity on both the adaptive and the innate immune

responses

Pidotimod decreases the in vitro expressionof CD30

Peripheral blood mononuclear cells from 13 atopic asthmatic vs. 9 normal children Mithogenesis in vitro

Pidotimod � ⇓ CD30 (associated with Th-2 cells)

Pidotimod affects the Th-1/Th-2 balance in atopic asthma.

Gourgiotis D. Immune modulator pidotimod decreases the in vitro expression of CD30 in peripheral blood mononuclear cells of atopic asthmatic and normal

children. J Asthma. 2004;41:285-7

S

Macrophage

NK-cells

Biological activities of Pidotimod in experimental studies

N

H

C

O COOH

N

PidotimodPidotimod

Macrophage

T-cells Neutrophils

I.G.G.I.G.G.I.G.G.I.G.G.Courtesy of Giovanni Rossi MD

.





5. I BRM possono agire sull’immunità naturale



Phagocytosis and intracellular killing of bacteria by human blood neutrophils and alveolar

macrophages

Neutrophil

Oddera et al. Drugs Exp Clin Res 1993; 19: 27-35.I.G.G.I.G.G.I.G.G.I.G.G.

Alveolar macrophage

Bacteria+ Dapi = alive

PI = dead

Pidotimod

Fluorescencemicroscopy

Courtesy of Giovanni Rossi MD

Activity of Pidotimod on phagocytosis and intracellular killing of S. aureus by human

polymorphonuclear leukocytes

30

24

18

% b

acte

ria/c

ell

Phagocytosed

Killed

**p<0.05

18

12

6

0

% b

acte

ria/c

ell

*

Controls Pidotimod Pidotimod Pidotimod1 mg/ml 10 mg/ml 100 mg/ml

**

Oddera et al. Drugs Exp Clin Res 1993; 19: 27-35.Courtesy of Giovanni Rossi MD

Activity of Pidotimod on H2O2 production by human

polymorphonuclear leukocytesH

2O2

prod

uctio

n

* =p<0,05

50

40

30

TPA

Medium

*

Oddera et al. Drugs Exp Clin Res 1993; 19: 27-35.

H2O

2 pr

oduc

tion

*

30

20

10

0

Controls Pidotimod Pidotimod Pidotimod1 mg/ml 10 mg/ml 100 mg/ml

*


Pidotimod synergized with cefotaxime in protecting mice against bacterial infections

Pidotimod+ Cefotaxime+ControlsPidotimodCefotaximePidotimod + Cefotaxime

100

80

% o

f sur

viva

l

Coppi et al. Arzneim Forsch Drug Res 1994; 44: 1417-21. I.G.G.I.G.G.I.G.G.I.G.G.

60

40

20

0

% o

f sur

viva

l

E. coli

60

100

90

P. vulgaris

40 40

0

100 90

P. mirabilis

50

200


Partial protective effect on experimental Coxsackie virus-induced infections in mice

100

80

60

Pidotimod25-100 mg/kg+

Dianzani et al. Arzneim Forsch Drug Res 1994; 44: 1431-33

60

40

20

0

% s

urvi

val

0 1 2 3 4 5 6 7 8 9 10

Controls

Pidotimod 25 mg/kg

Pidotimod 50 mg/kg

Pidotimod 100 mg/kg

DaysI.G.G.I.G.G.I.G.G.I.G.G.Courtesy of Giovanni Rossi MD

Protective effect on experimental Influenza virus-induced infections in micePidotimod

25-100 mg/kg+

100

80

60

% s

urvi

val

Dianzani et al. Arzneim Forsch Drug Res 1994; 44: 1431-33

60

40

20

0

% s

urvi

val

0 1 2 3 4 5 6 7 8 9 10

Controls

Pidotimod 25 mg/kg

Pidotimod 50 mg/kg

Pidotimod 100 mg/kg

Days


Clinical evaluation and changes in ciliary clearance after Pidotimod (PID) in Greek children with

recurrent repiratory tract infections

• Clinical evaluation• N° of RTI

A. 32 children(active group) PID

400 mg bid x 15 days + PID 400 mg od x 20

• N° of RTI(at 9 months)

Aivazis V. Minerva Pediatr 2002, 54: 315-319

Children (2.5-12 yrs) with >3 URTI or LRTI in the last 6 months

mg od x 20 days

B. 18 children(control group)

I.G.G.I.G.G.I.G.G.I.G.G.

• Changes in ciliary clearance

(at 6 months)


Number of respiratory tract infections inchildren treated with Pidotimod and controls

100

80

60%

of p

atie

nts

Children with > 3 RTI

p < 0.001***

Aivazis V. Minerva Pediatr 2002, 54: 315-319 I.G.G.I.G.G.I.G.G.I.G.G.

40

20

0

% o

f pat

ient

s

Pidotimod Controls(4/32) (10/18)

12.5

66.7

**


Respiratory epithelium ciliary clearance inchildren treated with Pidotimod and controls

Pidotimod

Controls75

60

45

Mea

n tim

e (M

T)

+ S

D

A. Respiratory epithelium clearance

p<0.001

Aivazis V. Minerva Pediatr 2002, 54: 315-319

30

15

0

Before 1 month 6 monthtreatment after after

Mea

n tim

e (M

T)

+ S

D

37.2 33.219.2

36.232.2 31.2

Before 1 month 6 monthtreatment after after


Efficacy of Pidotimod administration in the acute phase of URTI: a) Pyrexia; b) Antibiotic therapy; c) Absence from school

15

12

9

Day

s (n

umbe

rs)

Pidotimod

Placebo

**

**

9

6

3

0

Day

s (n

umbe

rs)

4.56.1

8.010.5

11.113.3

p < 0.01

**

**

Pyrexia Antibiotic therapy Absence from school

Caramia G. Arzneim-Forsch/Drug Res.1994; 44: 1480-82 I.G.G.I.G.G.I.G.G.I.G.G.

.






6. Concludo


Conclusions

• Clinical trials show the efficacy of BRMs in reducing the recurrency of upper and lower RTI in children

• Both bacterial lysates and Pidotimod, administered to childrenwith RRI, may lead to a better clinical outcome

• Further studies on BRMs are needed to:

- Better characterize the mechanisms of action

- Confirm the clinical efficacy in multicenter international trials

.






6. Concludo

7. Post-concludo

Post-scriptum

Questa notte ho riflettuto - e ho buttato giù di getto quattro righe in stile arguto. Solo un piccolo sonetto

in onore del baffuto - Presidente quasi-eletto.

E rompendo irritualmente - il silenzio elettoraleE rompendo irritualmente - il silenzio elettoralemi riporto con la mente - al programma magistraleche da vicepresidente - nel mandato quadriennale

ho collaborato a fare. Dal lavaggio delle manialle spiagge sopra il mare, dalle orecchie ai denti saniai vaccini da impostare - fino a temi anche più strani:

Post-scriptum

il bambino capriccioso, i pidocchi sulla testa, il fratello litigioso e l’obesità che infesta,

il tabacco che è dannoso, …. non so più che cosa resta.

Vorrei avere la sua verve nel portar le iniziative sempre oltre le riserve, le prudenze più retrive.

se di voti farà il pieno sarà un record senza meno:

e così il terzo mandato e la sua delega in bianco con l’ardor certificato di Caudillo non mai stanco sarà accolto dal boato: W il nostro Pino Franco!

immunomodulatori: come agiscono? - sipps · clinical evaluation and changes in ciliary clearance...

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