Phagocytic Activity of the Leukemic Cell and Its Response to the Phagocytosis-stimulating Tetrapeptide, Tuftsin
作者： Vilas Likhite , Victor A. Najjar , Andreas Constantopoulos , William H. Crosby
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摘要: DivisionofProteinChemistry[A.C.,V.A.N.J,DepartmentofMolecularBiologyandMicrobiology,TuftsUniversitySchoolofMedicine,andTheDepartmentofPediatrics[V.A.N.]andMedicine[V.L.,W.H.CJ,NewEnglandMedicalCenter,Boston,Massachusetts02111SUMMARYThephagocyticactivityofthreetypesofleukemiccellswasstudiedforStaphylococcusaureusinphysiologicalKrebs-Ringerphosphateglucosemediumalone,andafterstimulationwithautologouscomplement-inactivated serumandwithphagocytosis-stimulatingtetrapeptide,"tuftsin."Theleveloftuftsinactivityintheseraofpatientswasalsoevaluated.Fifteenpatientswereincludedinthisstudy:sixwithmyelofibrosis,sevenwithacutegranulocyticleukemia,andtwowithmyelomonocytic leukemia.Inallsixcasesofmyelofibrosis,thepolymorphonuclearcellsshowedanormallevelofbasalphagocytosisinKrebs-Ringerphosphateglucosemedium.Fiveofsevencasesofacutegranulocyticleukemiashowednormalornear-normalvaluesalso,whiletwohadsignificantlydiminishedlevels.Allthirteenofthesepatientsfailedtoshowstimulationwithsaturatingamountsofautologousserumortuftsin.Thisisdistinctlyabnormal,sincenormalbloodgranulocytesofhumans,dogs,andrabbitsareconsiderablystimulated.ThetwocasesofmyelomonocyticleukemiaavailableforstudyshowedahigherthannormalbasalphagocyticactivityinKrebs-Ringerphosphateglucosemediumandrespondednormallytoserumandtuftsinstimulation.INTRODUCTIONItisgenerallyrecognizedthatinfectionisamajorcauseofdeathinpatientswithWBCdyscrasias(4,12,15,18).Thebasicabnormalitiesofthediseaseareoftenworsenedbychemotherapeutic insultswhichpredisposethepatienttoavarietyofrepeatedandoftensevereinfections.Drugtherapyhasconsiderablyprolongedthelife-spanofmanypatients,butoptimalmanagementcontinuestodependonthejointmobilization ofantileukemicandantimicrobialtherapy.Patientswithadvancedmyelofibrosisbecomesusceptibletoinfectionasdopatientsinlatestagesofgranulocytic.leukemia(11).Duringthepastfewyearswehaveinvestigatedthe'SupportedbyGrantAI-09116,NIH,USPHS.andGrantGB-31535X,NationalScienceFoundation.'AmericanCancerSocietyProfessorofMolecularBiology(MADivision),towhomreprintrequestsshouldbeaddressed,atDivisionofProteinChemistry,TuftsUniversitySchoolofMedicine,136HarrisonAvenue,Boston,Mass.02111.ReceivedAugust14,1972;acceptedMarch5,1973.importantroleofcertainspecificcytophilic7-globulinsinstimulatingphagocytes.Aleukophilicfractionof-/-globulin,termedleukokinin(5,6)coatsthePMN3cellandenablesittoexhibitahighlevelofphagocytosis.AstudyofthemechanismofleukokininactiononthePMNcellrevealedthatitsbiologicalactivityresidesfullyinasimplepeptidewhichformsanintegralpartoftheleukokininmolecule.Thispeptide,whichwehavechristened"tuftsin,"(7,9)hasbeenisolated,itsstructuredetermined,andthecompoundsyntheszied(9).Itiscomposedof4aminoacidresidueswiththesequenceofthreonyllysylprolylarginine. Itisactiveinhormone-likequantitiesandwasfoundtobedeficientincertainpatientswithrepeatedinfections,inthosewith"tuftsindeficiencysyndrome"(3),andinsplenectomizedsubjects(7).ThephagocyticactivityofPMNleukocytesfrompatientswithacutegranulocyticleukemiahasbeeninvestigatedrepeatedlywithvariableresults(1,10,13,14,16,17).Studiesofpatientswithmyelofibrosishavenotbeenreported.MoststudiesofPMNgranulocyteswereperformedinthepresenceofautologousornormalserum,circumstancesinwhichadeficiencyofcertainhumoralfactorssuchasleukokininortuftsincouldhave beenmissed.Ithasnot possibletodeterminewhetherthephagocyticdeficiencywasinherentinthegranulocyteitselforinvolvedserumfactors,orboth.Sincewenowdifferentiatebetweenthesepossibilities,astudywasundertakenofleukocytesfrompatientswithacutegranulocyticleukemiaandwithmyelofibrosis.First,weexaminedtheresponsivenessofthePMNcellsofthesepatientstophagocyticstimulationbycomplement-inactivatedautologousserumandsynthetictuftsin.Second,weinvestigatedtuftsinlevelsinserumduringtheactivestageofthedisease.MATERIALSANDMETHODSSevenpatientswithacutegranulocyticleukemia,2withacutemyelomonocytic leukemia,and6withmyelofibrosiswerestudied(Table1).Thediagnosiswasbasedonclinicalfindings,peripheralbloodfilms,andbonemarrowmorphology,alongwithcytochemicalidentificationofgranulocytesandmonocytes(19).Inallpatientswithmyelofibrosis,bonemarrowbiopsieswereperformed.Twelvehealthyindividualsofbothsexes,24to68yearsold,wereusedascontrols.Usually,15mlofheparinizedbloodand5mlofclottedblood'Theabbreviationsusedare:PMN,polymorphonuclear;KRPG,Krebs-Ringerphosphateglucose.1230 CANCERRESEARCHVOL.33
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