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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
.
1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?
2. I bambini a rischio
33.. 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
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
.
1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?
2. I bambini a rischio
3. I BRM possono agire sull’immunità innata
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
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
.
1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?
2. I bambini a rischio
3. I BRM possono agire sull’immunità innata
4. I BRM possono agire sull’immunità adattiva
5. I BRM 5. I BRM possonopossono agireagire sull’immunitàsull’immunità naturalenaturale
6. 6. ConcludoConcludo
7. Post7. Post--concludoconcludo
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
.
1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?
2. I bambini a rischio
3. I BRM possono agire sull’immunità innata
4. I BRM possono agire sull’immunità adattiva
5. I BRM possono agire sull’immunità naturale
6. 6. ConcludoConcludo
7. Post7. Post--concludoconcludo
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
*
I.G.G.I.G.G.I.G.G.I.G.G.Courtesy of Giovanni Rossi MD
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
Courtesy of Giovanni Rossi MD
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
I.G.G.I.G.G.I.G.G.I.G.G.Courtesy of Giovanni Rossi MD
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)
Courtesy of Giovanni Rossi MD
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
**
Courtesy of Giovanni Rossi MD
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
I.G.G.I.G.G.I.G.G.I.G.G.Courtesy of Giovanni Rossi MD
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.
.
1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?
2. I bambini a rischio
3. I BRM possono agire sull’immunità innata
4. I BRM possono agire sull’immunità adattiva
5. I BRM possono agire sull’immunità naturale
6. Concludo
7. Post7. Post--concludoconcludo
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
.
1. Cosa sappiamo oggi sulle infezioni respiratorie recidivanti?
2. I bambini a rischio
3. I BRM possono agire sull’immunità innata
4. I BRM possono agire sull’immunità adattiva
5. I BRM possono agire sull’immunità naturale
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!
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