The effect of platelet-activating factor (PAF) antagonists and somatostatin analogues on lymphocytes and natural killer (NK) cell cytotoxicity

PROSTAGLANDINS

PLhlmm-AcTIvA~F~(PAF)-m~rlN-oRL~

¶TiEEFFmxoF

AmIafmqL~(~nr)~~m.

FarkasG. , Mandi Y. , geleli I. and K+oltai M.$ $ , University Medical School, Szeged, Department of Surgery , Microbiology and Pharmacology Hungary. The modulationof cell cytotoxicity by variousPAF antagonistsand two somatostatinanalogues(BIM 23014 and BIM 23026) was examined in two different systems.In the first system, involvingthe killingof Langerhansisletsby cytotoxicspleniclymphocytes,the cytotoxicreactionwas inhibited by the ginkgolidePAF antagonistBN 52021 (30 and 100 p&l),and the somatostatinanaloguesBIM 23014 and BIM 23026 (0.1 @I) when these drugs were added individually. A concentration of 10 pI.l BN 52021 was ineffectivealone, but when combinedwith either somatostatinanaloguea synergisticprotective effect on the destructionof Langerhansislets by cytotoxicsplenic lymphocyteswas observed.In the second model, the PAF antagonistsBN 52021, BN 52024 (a ginkgolidedevoid of PAF antagonistic activity)and WEB 2086 (an antagonistof PAP belongingto the triazolobenzodiazepine series) and the somatostatinanalogueBIN 23026 were evaluatedfor their effects on the lysis of K 562 target cells by human NK cells.Lysis was decreasedwhen eitherBN 52021 or BIM 23026 was introducedinto the systemat concentrations of 10 W to 0.1 nM or 10 nM to 0.1 @I, respectively.In contrast,BN 52024 was almost ineffectiveand WEB 2086 (0.1-0.5pJ4)exerted intermediate effects.BIM 23026 (1 W-10 @l), not only inhibitedNK cytolysisbut exhibiteda synergisticeffectwith BN 52021 (1 @l). Kineticanalysis showedboth substancesblocked an early event in the lytic process,a decreasein lysis only being observedwhen the drugs were added within the first hour of the assay. Together these data implicatePAF in the regulationof cell cytotoxicityand indicatethat antagonistsof this autacoid,togetherwith somatostatin, may be beneficalin the treatmentof inmunopathological processessuch as autoinmunediabetesand graft rejection.

CONPARISOH RAT

:

OF SYSTEMIC AND LOCAL EOSINOPHIL RECRUITNENT

A. Etienne, 91952

INDUCED BY PAF OR IWINE

CHALLENGE

IN

THE

NODlJlATION BY DRU6S. C.

Soulard,

F. Thonier

IHB Research Labs

- 1, ave

des Tropiques

-

LES ULIS CEOEX - FRANCE.

The factors

responsible

volved

in regulating

creased

chemotaxis,

for eosinophil recruitment

decreases

for human eosinophils

in density and surface

in the peritoneal

clophosphamide.

tatin analog BIH 23014 and of cyclosporin cant increase of eosinophil at time 24 h than

at 4 h. CsA

BN 52021 (25 mg/kg t 4 h). Similarly peritoneal

count

and circulating

(25 mg/kg p.o.) almost

peritoneal eosinophil challenge

in actively

eosinophil counts at 4 h, and

increase

little effect on circulating which are involved cell availability ting PAF-induced

infiltration.

In contrast, the

chemotaxis.

between drugs acting on eosinophils

of hematopoietic

p <

0.01,

increased aboli-

(- 86 %, p < 0.5).

cells into eosinophils,

In

relatively

proliferation, thus

decreasing

PAF antagonist primarily would act by

These animals models seem

effect whereas

BIM 23014 significantly

cells. CsA and somatostatin are known to affect T-cell

for recruitment.

perito-

with a higher extent at 24 h. CsA

peritoneal eosinophil recruitment, while having

in the differentiation

eosinophil

(- 75 X,

sensitized animals

(- 68 %, p < 0.001) and cell infiltration

eosinophils

incy-

somatos-

levels with a higher

reduced

BN 52021 primarily decreased

and

totally abrogated these variations

and peritoneal eosinophil

the circulating

these

with sephadex or

BN 52021, the

shed totally both hypereosinophilia contrast,

of

(CsA) was studied on these models. PAF induced a signifi-

PAF, peritoneal antigen

and circulating

in-

agent

induced by PAF or antigen

by pretreatment

of the PAF antagonist,

both at peritoneal

~.a.) reduced essentially to

of the recruitment

and 24 h after challenge for circulating

cell count analysis. The activity

in-

reactions.

compare eosinophil mobilization

cavity of rats made hypereosinophil

Rats were killed 15 min, 4 h

appear to be

charge). PAF is a powerful chemotactic

feature of immediate type hypersensitivity

The aim of the present study was to

neal differential

poorly defined. Cytokines

cellular changes (enhanced cytotoxicity,

suggesting that this mediator may be responsible

Cells, a characteristic jection

are

this process and the accompanying

to be relevant to

inhibi-

discriminate

with dissimular modes of action.

MAY

1988 VOL.

35 NO. 5