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849

Pyroptosis, production of reactive oxygen species and synthesis of

nitric oxide, and inflammatory response were activated in survival

patients at D0 and D7. Furthermore, bacterial infection inhibition

was found in survivals. Interestingly, similar functions were also

identified in non-survivals but differences were the activation

or inhibition z scores. These results highlight the activation of

inflammasome during sepsis, with a different degree of modulation

in survivors and non-survivors. Further validation of some genes at

protein level is under process.

AS01-adjuvanted vaccine induces a transient innate immune

response in humans

Smolen, K.

1

, Herve, C.

2

, Brouwer,M.

1

, Taton,M.

1

, Auquier, P.

2

, Fissette, L.

2

,

Marchant, A.

1

, Van Belle, P.

2

, Burny, W.

2

, Didierlaurent, A.

2

, Willems, F.

2

1

ULB,InstituteforMedicalImmunology,Gosselies,Belgium,

2

GSK,

Rixensart,Belgium

AS01 is an Adjuvant System containing 3-

O

-desacyl-4’-

monophosphoryl lipid A (MPL),

Quillaja saponaria

Molina, fraction

21(QS-21) and liposome. AS01 has been selected for the clinical

development of several candidate vaccines including the malaria

and varicella zoster vaccine. AS01 promotes both humoral and

cellular responses. Yet, little is known about the immunological

mechanisms in humans by which AS01 induces effective immune

responses. Given the fundamental role of the innate immune

system in controlling the adaptive immune responses, we have

conducted a phase II randomized, single centre, single-blind study

(NCT01777295) to characterize the kinetics of the early immune

response to immunizationwithanAS01-adjuvantedvaccine.

60 HBV-naive adults (18-45 years old) received 2 doses of Hepatitis

B virus surface antigen (HbsAg) adjuvanted with AS01 B (50µg

MPL, 50µg QS-21) or aluminium hydroxide at days 0 and 30. All

subjects received a saline placebo (baseline) 30 days prior vaccine

administration.Whole blood samples were collected at defined time

points (0h to 7 days) before and after placebo, dose 1 and dose2.

Immunization with AS01 B -adjuvanted vaccine leads to an early

and transient inflammatory response in blood, characterized by

changes in some cytokines, innate cell number and activation.

Cellular variations were specifically reflected in monocyte subsets-

particularly intermediate monocytes- and NK cells, indicative of

the stimulation of the innate immune system. Although restricted

to HBsAg and a naive population, identification of these early

signatures may provide new insights into the mechanisms of AS01-

adjuvantedvaccineinducedprotectiveimmuneresponse.

Analysis of

CTLA-4

gene polymorphisms (-319 C/T, +49 A/G,

CT60 G/A) in primary Sjögren´s syndrome

Carrillo-Ballesteros,F.J.

1

,Muñoz-Valle,J.F.

1

,Palafox-Sánchez,C.A.

1

,

Valle,Y.

1

,López-Villalobos,E.F.

1

,Badial-Hernández, M.F.

1

,Hernández-

Martínez,M.A.

1

,Rodríguez-Machuca,V.U.

1

,Vázquez-Villamar,M.

1

,

Orozco-Barocio,G.

2

,Oregon-Romero,E.

1 1

UniversidaddeGuadalajara,

InstitutodeInvestigaciónenCienciasBiomédicas(IICB),Guadalajara,

Mexico,

2

HospitalGeneral deOccidente,SSJ.,Zapopan,Mexico

Introduction:

Primary Sjögren´s syndrome (pSS) is an autoimmune

disease affecting salivary and lacrimal glands. It is characterized

by a progressive lymphocytic infiltration, mainly T cells. Cytotoxic

T-Lymphocyte Antigen 4 (CTLA-4) plays a critical role in the

prevention of autoimmune pathology by a critical inhibitory role in

T cell responses resulting in diminished proliferation and cytokine

production. Polymorphic sites located at -319C/T, +49A/G and

CT60G/A in the

CTLA-4

gene have been associated with elevated

CTLA-4 serumlevels (sCTLA-4) andautoimmunity.

Objective:

Determine the frequency of CTLA-4 polymorphism in pSS.

Methodology:

The study included 111 Mexican mestizo patients

with pSS, classified according to the American-European Consensus

criteria. As control group, 122 clinically healthy subjects were

included. The polymorphisms were genotyped by PCR/RFLP

technique. Statistical analysis was carried out with

Pasw statistics

18

andEmHapFre softwares.

Results:

Polymorphisms were in Hardy-Weinberg equilibrium

and showed moderate linkage disequilibrium

(50%, p=0.009)

. The

most frequent haplotypes were: CAG(34%), CAA(26%), CGG(18%),

and CGA(17%). Patients that carried CAA haplotype showed high

sCTLA-4levels,lymphocyticinfiltratedandautoantibodyproduction

without statistic significance. Inaddition, high levelsof sCTLA-4were

observed inpSSpatients carriers of -319CT genotype (p=0.018

vs

CC)

and+49AAgenotype

(p=0.013

vs

GG).

Conclusion:

Our results suggest that

CTLA-4

polymorphisms -319

and +49 could have a role for the development of pSS. However, the

lowassociations of sCTLA-4with clinical parameters suggest that the

potentialeffectof

CTLA-4

polymorphisms needs tobe investigated in

subsequent studies inMexican patients in order to elucidate it.

Simple and effective tumour immunotherapy using

intratumoural complete Freund´s adjuvant

Fahrer,A.

1

,Carroll,C.

1

,Andrew,E.

1

,Orange,M.

2

,Allavena,R.

3

1

TheAustralianNationalUniversity,ResearchSchoolofBiology,Acton,

Australia,

2

ArlesheimKlinik, Onkologie, Arlesheim, Switzerland,

3

University

of Queensland, School of Veterinary Science, Gatton, Australia

We demonstrate that intra-tumoural injection of Complete Freund´s

Adjuvant can result in a potent anti-tumour immune response. In

order to test the efficacy of this treatment, we have initiated pre-

clinicaltrialsinthreespecies:mice,dogsandhorses.Efficacy hasbeen

demonstrated in a range of solid tumours, including mastocytoma,

mammary tumours and melanoma. Complete tumour regressions

have been observed in all three species. Evidence of systemic

immune responses (regression of non-injected metastases) have

also been observed. We characterise the immune cells infiltrating

mouse tumours after treatment. Finally we provide case reports on

the treatment of four human cancer patients; suffering from lung

cancer, metastatic osteosarcoma, or breast cancer, with one patient

havingapartial response to treatmentwith intra-tumoural Complete

Freund´s Adjuvant.

Taken together, our data demonstrate that our treatment has major

anti-tumour effects in a proportion of treated animals, and is safe for

use inhumancancer patients. Further trials inhumancancer patients

are therefore strongly warranted. Our novel treatment provides a

simple and inexpensive cancer immunotherapy, applicable toawide

range of solid tumours, and of potential benefit to cancer patients

around theworld, includingpatients fromdeveloping countries.