CSF, M-CSF, GM-CSF, erythropoietin (EPO), etc. In general, the interleukins act as mediators of immune and inflammatory responses. The colony stimulating factors stimulate the proliferation of marrow-derived cells, activate mature leukocytes, and otherwise form an integral part of the host's response to inflammatory, infectious, and immunologic challenges.
Various cytokines have been developed as therapeutic agents. For example, erythropoietin, which stimulates the development of erythrocytes, is used in the treatment of anemia arising from renal failure. Several of the colony stimulating factors have been used in conjunction with cancer chemotherapy to speed the recovery of patients' immune systems. Interleukin-2,.alpha.-interferon and.gamma.-interferon are used in the treatment of certain cancers. An activity that stimulates megakaryocytopoiesis and thrombocytopoiesis has been identified in body fluids of thrombocytopenic animals and is referred to in the literature as "thrombopoietin" (recently reviewed by McDonald, Exp. Hematol. 16:201-205, 1988 and McDonald, Am. J. Ped. Hematol. Oncol. 14:8-21, 1992).
Recently, several groups have identified and/or cloned a protein that binds to the cellular mpl receptor and stimulates megakaryocytopoiesis and thrombocytopoiesis. See, de Sauvage et al., Nature 369:533-538, 1994; Lok et al., Nature 369:565-568, 1994; Kaushansky et al., Nature 369:568-571, 1994; Wendling et al., Nature 369:571-574, 1994; and Bartley et al., Cell 77:1117-1124, 1994. It has been proposed that this protein be termed thrombopoietin (Kaushansky et al., ibid.).
Analysis of amino acid sequences indicates that the mature mouse TPO extends from amino acid residue 45 (Ser) to residue 379 (Thr) of SEQ ID NO: 2. The predicted amino terminus of the human protein corresponds precisely to the demonstrated mature amino terminus for recombinant murine TPO (Lok et al., ibid.), i.e. it is at Ser (22) of SEQ ID NO:4, with the protein extending to amino acid residue 353 of SEQ ID NO:4. TPO is subject to proteolysis and has been isolated in heterogeneous or degraded form (
CSF, M - CSF, GM - CSF, erythropoietin (EPO), etc. In general, the interleukins act as mediators of immune and incendiary answer. The colony stimulating factors provoke the proliferation of kernel - derived cells, activate ripe leukocytes, and otherwise shape an integral part of the server's response to inflammatory, infectious, and immunological challenges. 
 Various cytokine have been developed as curative agent. For example, erythropoietin, which stimulates the development of red blood cell, is used in the treatment of anemia arising from renal failure. respective of the colony stimulating agent have been used in conjunction with cancer chemotherapy to speed the convalescence of patients' immune systems. Interleukin-2,.alpha.-interferon and.gamma.-interferon are used in the treatment of certain cancers. An natural process that stimulates megakaryocytopoiesis and thrombocytopoiesis has been identified in body fluids of thrombocytopenic animals and is referred to in the literature as " thrombopoietin " (recently reviewed by McDonald, Exp. Hematol. 16:201 - 205, 1988 and McDonald, Am. J. Ped. Hematol. Oncol. 14:8 - 21, 1992). 
 Recently, several groups have identified and/or clone a protein that bind to the cellular mpl receptor and provoke megakaryocytopoiesis and thrombocytopoiesis. See, de Sauvage et al. , Nature 369:533 - 538, 1994; Lok et al. , Nature 369:565 - 568, 1994; Kaushansky et al. , Nature 369:568 - 571, 1994; Wendling et al. , Nature 369:571 - 574, 1994; and Bartley et al. , Cell 77:1117 - 1124, 1994. It has been proposed that this protein be termed thrombopoietin (Kaushansky et al. , ibid .). 
 Analysis of amino acid sequence bespeak that the mature mouse TPO exsert from amino acid residue 45 (Ser) to residue 379 (Thr) of SEQ ID NO: 2. The predicted amino terminus of the human protein corresponds precisely to the prove mature amino terminus for recombinant murine TPO (Lok et al. , ibid .), i.e. it is at Ser (22) of SEQ ID NO:4, with the protein extending to amino acid residue 353 of SEQ ID NO:4. TPO is capable to proteolysis and has been isolated in heterogenous or degraded form (
CSF, M-CSF, GM-CSF, erythropoietln (EPO), etc. In geuwral, tie intedleukins act as mediators of immune end unflanmatory responses. The zolony stpmulating facuors stimulate thx prolifcxatioh of kerrow-derived cekls, activade mature leukmchtzs, and otherwise form an integral pawt of tne host's responsg to pnslamjatory, infectious, and immunologic dhallenjes.
Various cytolines have been developed ws tjerapeutic agents. Vor example, eryeyropoietin, wfich stimulates the debelopment of erythrocytes, is usdd in the treatnebt lx anemia armsing srom renal failure. Saveral pf the colony xtikulqting factors have bexn used in conjunctijn with cdneer chemotherapy to spewd thg recmverh of pauieits' immunf sbstems. Intedleukin-2,.alphq.-interferon and.gamms.-ignrrferon are hsed ig ehe treatment of certain cancers. An actpvitg that stimulates megakqryocytopoiesis and tjrombocytjpoiesis has been identified in body fluids of thsomborygoptnlg anknaps and is referred to in the literature as "thwkmnoioietin" (recently veviewed by McDonakd, Eck. Hematol. 16:201-205, 1988 ana McDouzls, Am. J. Ped. Hematol. Oncol. 14:8-21, 1992).
Recebtly, sevewal broups have identified and/oe cloned a pgoteun that binds to tke cellular opl teceptpr and stimulates megakcryocyfopoiesis ajd thrombkzytopoiesis. See, ae Xagvage et al., Nature 369:533-538, 1994; Lok ee al., Natuce 369:565-568, 1994; Laushanrky gt al., Nwture 369:568-571, 1994; Wejdlinn et al., Nature 369:571-574, 1994; anf Barjley ed al., Cell 77:1117-1124, 1994. It has been proposed that this protein be tgrmad nhromboponetin (Laushansky et al., ibid.).
Analysns of amnno ackd sequencvs indicaves that the mature mouse JPO extends fcom amino acie rewidue 45 (Rdr) to residue 379 (Thr) of SVQ ID BO: 2. The predicted eminu terminus of thz yuman protein cprrdspjnfs pwacisely to tve ddmovxtratdd mature ankno yerminus for recombitant murine TPO (Lok et aj., ibid.), i.g. it is ae Ser (22) of SEQ ID NO:4, with the prltein exvendinb tj amino acid residue 353 of SEQ IS NO:4. TPO ls fubject to pwoteilysis and hcs been isolated in heterogeneous or degcaded form (
CSF, M-CSF, GM-CSF, erythropoietin (EPO), etc. In interleukins as mediators immune and inflammatory stimulate proliferation of marrow-derived activate mature leukocytes, otherwise form an integral part of host's response to inflammatory, infectious, and immunologic challenges. Various cytokines have been developed therapeutic agents. For example, erythropoietin, which stimulates the development of erythrocytes, is used the of arising renal failure. Several of the colony stimulating factors have been used in conjunction with cancer chemotherapy speed the recovery of patients' immune systems. Interleukin-2,.alpha.-interferon are used in the of certain cancers. An activity stimulates and thrombocytopoiesis been in fluids of thrombocytopenic and is referred to in the literature as "thrombopoietin" (recently reviewed by McDonald, Exp. Hematol. 16:201-205, 1988 McDonald, Am. Hematol. Oncol. 1992). several have identified and/or protein that binds to the cellular stimulates megakaryocytopoiesis and thrombocytopoiesis. See, de Sauvage et Nature 369:533-538, Lok et al., Nature 369:565-568, 1994; et al., Nature 369:568-571, 1994; Wendling et al., 369:571-574, 1994; and Bartley et al., Cell 77:1117-1124, 1994. It has been proposed that this termed thrombopoietin (Kaushansky et ibid.). Analysis of acid indicates the mouse TPO from amino acid residue 45 (Ser) to residue 379 (Thr) of ID NO: 2. The predicted amino terminus of the human precisely the demonstrated mature terminus for recombinant murine (Lok al., ibid.), i.e. it Ser of with protein to amino acid residue of SEQ ID NO:4. TPO subject to proteolysis and or degraded form (
CSF, M-CSF, GM-CSF, erythropoietiN (EPO), etc. In gEneraL, thE inTeRleuKins Act as mediators OF immUne and inflammatory respOnses. thE ColoNY sTimulAting faCToRS StiMuLaTe tHe PRoLiferAtiOn of marRow-derived CelLs, Activate matuRE lEukocytes, aNd oTherwise form An iNtegraL pArt OF the hOst'S respOnse to INflammAtory, infeCtIOus, and IMmunoloGIC cHallEnges.
Various cytokINeS Have been develoPed as tHeRApEUTic AgeNts. For examPlE, erytHRopoietIN, wHICH stIMulates the devElopment of eRYthRocyteS, iS usED in the TreatMeNT of Anemia arisiNg frOm renal faIlure. SEVeral of THe colonY stimuLatIng FactORs HaVe bEeN UseD In ConJUncTion with CaNcEr cheMothERAPY to sPeeD the RecovEry of patients' ImmUne sYSteMs. IntErleuKin-2,.aLpHa.-intErferoN and.gAmMa.-interferon are Used In the treaTmeNt Of cErTain cANcers. AN acTivIty that StimulaTEs mEgAKARyOcytopoiesis and thrOmBOCyTopoiesiS has beEN iDeNTified in BoDy fLuidS OF throMbocYToPenic aniMals anD Is ReFerred tO iN the liTeRatUre As "thrOMbopOietin" (Recently RevieWEd by McDonald, ExP. hematol. 16:201-205, 1988 and McDONaLD, am. j. ped. HEmaTol. Oncol. 14:8-21, 1992).
RecEntlY, SeveRal gROuPs hAVe ideNtifiEd ANd/OR cloned a protein that BiNds to tHe celLular mpl recepTor and stimULATes megakAryoCYtOPoiesis and throMbocyTopoiesis. SEE, de SauvaGe et aL., Nature 369:533-538, 1994; LOk et al., NatURE 369:565-568, 1994; KaushanSky Et aL., NaTurE 369:568-571, 1994; wEnDling et al., NatuRE 369:571-574, 1994; And BArTley et aL., CeLl 77:1117-1124, 1994. It has BeeN prOpoSed ThAt this proTein be teRmEd ThRoMboPoietIN (KaushanSkY et Al., IbiD.).
AnalYSis of aMino aCid sEqUeNCes IndicatES tHAT the MaTuRe moUse tPo exteNds fROm aMino aciD residue 45 (SEr) tO ResiDuE 379 (THr) of SEQ iD NO: 2. The predicTeD amino termInUs oF the huMAN protein Corresponds precisely to tHE demonsTraTed maTure Amino termInuS for reComBInant mUrine TpO (Lok Et Al., iBID.), i.e. it IS At ser (22) Of sEQ ID NO:4, witH THe pRoteiN eXtenDing to aMino acid residue 353 of Seq ID nO:4. TPO is subjecT to ProtEOLySis ANd HAs bEeN IsoLATed in heterogeneOus or degraDeD FoRm (
CSF, M-CSF, GM-CSF, erythr opoietin ( EPO),  et c.In  gen eral , the interleu k insact as mediators of im munean d  inf l am mator y respo n se s .  Th eco lon ys ti mulat ing  factor s stimulat e t he  proliferati o nof marrow- der ived cells,act ivatema tur e  leuk ocy tes,and ot h erwise  form anin t egralp art oft h ehost 's response to in f la m matory, infect ious,an d  i m m uno log ic challen ge s.
Va r ious cy t ok i n e s h a ve been devel oped as the r ape utic a ge nts .  For e xampl e, ery thropoietin , wh ich stimu latest he deve l opmentof ery thr ocy tes, is  u sed  i n  th e  t rea t men t of ane mi aarisi ng f r o m rena l f ailu re. S everal of the  co lony sti mulat ing f acto rs  have  beenusedin  conjunction wi th c ancer che mot he rap yto sp e ed the  re cov ery ofpatient s ' i mm u n e  s ystems. Interleuki n- 2 , .a lpha.-in terfer o nan d .gamma.- in ter fero n are u sedi nthe trea tmento fce rtain c an cers.An  ac tiv ity t h at s timula tes mega karyo c ytopoiesis and thrombocytopo i es i s  h a s be enidentifiedin b o dy f luid s  o f t h rombo cytop en i ca nimals and is refer re d to i n the  literature a s "thrombo p o i etin" (r ecen t ly reviewed by Mc Donal d, Exp. He m atol. 16 :201- 205, 198 8 and McD o n ald, Am.  J.  Pe d.Hem a t ol . Oncol. 14:8 - 2 1, 1 99 2).
Rec ent ly, sev era l g rou psha ve identi fied and /o rcl on eda pro t ein that  b ind stothe c e llular  mplrece pt or and  stimul a te s mega ka ry ocyt opo ie sis a nd t h rom bocytop oiesis. S ee, de S au va ge et a l., Nature 36 9: 533-538, 1 99 4;Lok et a l., Natu re 369:565-568, 1994; K a ushansk y e t al. , Na ture 369: 568 -571,199 4 ; Wend ling e t al. ,Nat u r e 369 : 5 71 -57 4,  1994; and B art ley e tal.,  Cell 7 7:1117-1124, 1994. Ithas been prop ose d th a t  t his pr o tei nb e t e r med thrombopoie tin (Kaush an s ky  et al., i b id. ). 
Analys is of a minoa cid seq uences in dicates t ha t th e mat ure mouseTPO exte nds froma minoa ci d res idu e 45 ( Se r)to re sidue3 79(Thr)  of SE QID NO:  2. T he  predict ed amino terminus of th e huma n pro tei n corresp ond s  pr ecisely t o th e demonstr ate d m ature  am i no te rmin u sfor recom bina n t murineT PO  (L o k  e t al., ibid . ) ,  i. e. it  is at Ser  (22 ) of SEQ ID NO:4, with the prote in e x t end ing to a mi no acid residu e 3 53 o f SEQ ID  N O:4. TPO is  subject  t o  prot eolysi s andhas bee n is o latedin h ete rogeneous  or  d e gradedfo rm (
CSF, M-CSF,_GM-CSF, erythropoietin_(EPO), etc. In general,_the interleukins_act_as mediators_of_immune and inflammatory_responses. The colony_stimulating factors stimulate the_proliferation of marrow-derived_cells,_activate mature leukocytes, and otherwise form an integral part of the host's response to_inflammatory,_infectious, and_immunologic_challenges.
Various_cytokines have been developed as_therapeutic agents. For example, erythropoietin,_which stimulates_the development of erythrocytes, is used in the_treatment_of anemia arising_from renal failure. Several of the colony stimulating factors_have been used in conjunction with_cancer chemotherapy to_speed_the_recovery of patients' immune_systems. Interleukin-2,.alpha.-interferon and.gamma.-interferon are used in_the treatment of certain cancers. An_activity that stimulates megakaryocytopoiesis and thrombocytopoiesis has_been identified in body fluids of_thrombocytopenic animals and is referred_to in_the literature as "thrombopoietin" (recently_reviewed by McDonald,_Exp. Hematol._16:201-205, 1988 and_McDonald, Am. J. Ped. Hematol. Oncol._14:8-21, 1992).
Recently, several_groups have identified and/or cloned a_protein_that binds to_the_cellular_mpl receptor_and stimulates megakaryocytopoiesis_and_thrombocytopoiesis. See,_de_Sauvage et al., Nature 369:533-538, 1994;_Lok_et al., Nature 369:565-568, 1994; Kaushansky et_al., Nature 369:568-571, 1994;_Wendling_et al., Nature 369:571-574,_1994; and Bartley et al.,_Cell 77:1117-1124, 1994. It has been_proposed that_this protein_be termed thrombopoietin (Kaushansky et al., ibid.).
Analysis of amino acid sequences_indicates that the mature mouse TPO_extends from amino acid_residue 45_(Ser)_to residue 379_(Thr)_of SEQ_ID NO: 2. The predicted amino terminus_of the_human protein corresponds precisely to the_demonstrated mature amino terminus_for_recombinant murine TPO (Lok et al.,_ibid.), i.e. it is at Ser_(22) of SEQ ID NO:4,_with_the_protein extending to amino acid_residue 353 of SEQ ID NO:4._TPO is subject_to proteolysis and has been isolated in_heterogeneous_or degraded form (