SE461985B - IN VITRO IMMUNIZATION OF Lymphocyte-containing CELL POPULATIONS AND MATERIAL KIT - Google Patents
IN VITRO IMMUNIZATION OF Lymphocyte-containing CELL POPULATIONS AND MATERIAL KITInfo
- Publication number
- SE461985B SE461985B SE8803208A SE8803208A SE461985B SE 461985 B SE461985 B SE 461985B SE 8803208 A SE8803208 A SE 8803208A SE 8803208 A SE8803208 A SE 8803208A SE 461985 B SE461985 B SE 461985B
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- lysosomotropic
- cell populations
- vitro
- lymphocyte
- leucine
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
- C12N5/163—Animal cells one of the fusion partners being a B or a T lymphocyte
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/998—Proteins not provided for elsewhere
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Abstract
Description
461 985 10 15 20 25 30 35 2 år och det finns nu väl utvecklade in vitro immuniserings- system. 461 985 10 15 20 25 30 35 2 years and there are now well-developed in vitro immunization systems.
Det som dock kännetecknar dessa system är att de till övervägande delen resulterar i en primär immuni- sering med produktion av antikroppar av IgM-typ. Olika metoder har testats för att i ett in vitro system få till stånd en övergång från IgM- till IgG-produk- tion, vilket in vivo sker naturligt för de flesta antigen.However, what characterizes these systems is that they predominantly result in a primary immunization with the production of IgM-type antibodies. Various methods have been tested to bring about a transition from IgM to IgG production in an in vitro system, which occurs in vivo naturally for most antigens.
För de flesta antigen ger nuvarande in vitro immuniseringsteknik ett bra utbyte av specifika hybri- dom. Vid immunisering med tymusberoende antigen finns dessutom möjligheten att öka utbytet genom tillsats av någon typ av immunsvarsmodifierande medel, s k BRM (Biological Response Modifier). Vid s k tymus- oberoende antigen är det direkta utbytet oftast lägre, och de BRM som fungerar väl för tymusberoende antigen fungerar inte lika bra för tymusoberoende antigen.For most antigens, current in vitro immunization techniques provide a good yield of specific hybrids. In immunization with thymus-dependent antigen, there is also the possibility of increasing the yield by adding some type of immune response modifier, so-called BRM (Biological Response Modifier). In so-called thymus-independent antigen, the direct yield is usually lower, and the BRMs that work well for thymus-dependent antigen do not work as well for thymus-independent antigen.
I ett försök att undvika dessa problem har man tillsatt s k polyklonala aktivatorer, t ex endotoxiner, lektiner etc, vid immuniseringen. Nackdelen med detta förfarande är dock att dessa aktivatorer stimulerar alla celler i lymfocytpreparationen, dvs även de celler som har en suppressiv effekt på immuniseringen.In an attempt to avoid these problems, so-called polyclonal activators, eg endotoxins, lectins, etc., have been added during the immunization. The disadvantage of this method, however, is that these activators stimulate all cells in the lymphocyte preparation, ie also the cells that have a suppressive effect on the immunization.
För stimulering av humana lymfocyter har Borre- baeck et al (WO88/01642) utvecklat ett system vid vilket för in vitro immunisering oönskade celler avlägs- nas för att på så sätt öka det specifika utbytet av antikroppsproducerande hybridom. Metoden bygger på användningen av ett lysosomotropt agens som dödar alla lysosominnehállande celler.For stimulation of human lymphocytes, Borrebaeck et al (WO88 / 01642) have developed a system in which unwanted cells for in vitro immunization are removed, thus increasing the specific yield of antibody-producing hybridomas. The method is based on the use of a lysosomotropic agent that kills all lysosome-containing cells.
Det har nu överraskande visat sig att man genom att använda en kombination av metoden med lysosomotropa agens och stimulering med polyklonala aktivatorer kan öka utbytet av specifika hybridom och även av specifika IgG-producerande hybridom vid in vitro immuni- sering med såväl tymusberoende som tymusoberoende antigen. 10 15 20 25 30 35 461 985 3 Ett ändamål med föreliggande uppfinning är således att åstadkomma ett förfarande för ökning av utbytet av antigenpositiva hybridom och ökning av utbytet av IgG-producerande hybridom av antigenpositiva hybridom vid in vitro immunisering av lymfocytinnehållande cellpopulationer för framställning av monoklonala antikroppar.It has now surprisingly been found that by using a combination of the method with lysosomotropic agents and stimulation with polyclonal activators, the yield of specific hybridomas and also of specific IgG-producing hybridomas can be increased by in vitro immunization with both thymus-dependent and thymus-independent antigens. Thus, an object of the present invention is to provide a method for increasing the yield of antigen-positive hybridomas and increasing the yield of IgG-producing hybridomas of antigen-positive hybridomas in in vitro immunization of lymphocyte-containing cell populations to produce monoclonal antibodies.
Förfarandet enligt uppfinningen kännetecknas av att lysosomotropt agens, lysosomotropa derivat därav eller lysosomotropa substanser syntetiserade utifrån sådant agens bringas att verka in vitro på de lymfocytinnehâllande cellpopulationerna för bort- tagande av cellpopulationer med negativ inverkan på in vitro immuniseringen, varefter lymfocyterna immuni- seras in vitro med tymusberoende eller tymusoberoende antigen under samtidig närvaro av en polyklonal akti- vator i en suboptimal mängd.The method according to the invention is characterized in that lysosomotropic agents, lysosomotropic derivatives thereof or lysosomotropic substances synthesized from such agents are caused to act in vitro on the lymphocyte-containing cell populations to remove cell populations with a negative effect on the in vitro immunosoculation, thymus-dependent or thymus-independent antigen in the simultaneous presence of a polyclonal activator in a suboptimal amount.
Detta förfarande bygger således på att celler som är oönskade för immuniseringen avlägsnas med hjälp av ett lysosomotropt agens, varefter kvarvarande celler utnyttjas i ett traditionellt in vitro immuniserings- förfarande samtidigt som de stimuleras med en polyklonal aktivator. Koncentrationen av den polyklonala akti- vatorn är sådan att den polyklonala aktivatorn i sig själv inte förmår att stimulera cellerna till proli- feration, dvs en suboptimal mängd.This method is thus based on the removal of cells that are undesirable for the immunization by means of a lysosomotropic agent, after which the remaining cells are utilized in a traditional in vitro immunization procedure while being stimulated with a polyclonal activator. The concentration of the polyclonal activator is such that the polyclonal activator itself is not able to stimulate the cells to proliferate, ie a suboptimal amount.
De på detta sätt immuniserade cellerna fuseras därefter på traditionellt sätt.The cells immunized in this way are then fused in the traditional manner.
Som polyklonala aktivatorer kan t ex användas endotoxiner; lektiner, såsom PHA (Phytohaemagglutinin), PWM (Pokeweed Mitogen), Con A (Concanavalin A); Staphylo- coccus aureus celler; protein A eller protein G.As polyclonal activators, for example, endotoxins can be used; lectins such as PHA (Phytohaemagglutinin), PWM (Pokeweed Mitogen), Con A (Concanavalin A); Staphylococcus aureus cells; protein A or protein G.
Som lysosomotropt agens kan användas lysosomotropa aminosyraderivat eller peptider baserade på sådana derivat. Ett speciellt föredraget lysosomotropt agens är leucin-leucin-O-metylester eller peptider baserade på leucin-O-metylester. 461 10 15 20 25 30 35 985 4 Dessa lysosomotropa agens har den specifika för- mågan att döda alla lysosominnehållande celler, t ex monocyter/makrofager, NK-celler samt eventuellt andra för närvarande okända cellsubpopulationer, på mycket kort tid. Genom användningen av lysosomotropa agens kan man således på några tiotals minuter anpassa en lymfocytpopulation så att den kan användas vid in vitro immunisering för produktion av monoklonala anti- kroppar. Lymfocytpopulationens B-celler kan sålunda aktiveras antigenspecifikt utan negativ inverkan från lysosomalpositiva celler. På så sätt skapas en immun population lymfocyter som kan användas för framställ- ning av hybridom och för produktion av monoklonala antikroppar.Lysosomotropic agents can be used as lysosomotropic amino acid derivatives or peptides based on such derivatives. An especially preferred lysosomotropic agent is leucine-leucine-O-methyl ester or peptides based on leucine-O-methyl ester. 461 10 15 20 25 30 35 985 4 These lysosomotropic agents have the specific ability to kill all lysosome-containing cells, eg monocytes / macrophages, NK cells and possibly other currently unknown cell subpopulations, in a very short time. Thus, by the use of lysosomotropic agents, a lymphocyte population can be adapted in a few tens of minutes so that it can be used in in vitro immunization for the production of monoclonal antibodies. Thus, the B cells of the lymphocyte population can be activated antigen-specifically without adverse effects from lysosomal-positive cells. In this way, an immune population of lymphocytes is created that can be used for the production of hybridomas and for the production of monoclonal antibodies.
Förfarandet kan tillämpas på cellpopulationer av animaliskt ursprung. Exempelvis har försök utförda på murina lymfocytinnehållande cellpopulationer gett mycket goda resultat.The method can be applied to cell populations of animal origin. For example, experiments performed on murine lymphocyte-containing cell populations have given very good results.
Ett annat ändamål med uppfinningen är att åstad- komma en materialsats, s k kit, för användning vid in vitro immunisering av lymfocytinnehållande cellpopu- lationer. De med denna materialsats behandlade cell- populationerna kan sedan användas för produktion av monoklonala antikroppar.Another object of the invention is to provide a kit of material, so-called kit, for use in in vitro immunization of lymphocyte-containing cell populations. The cell populations treated with this kit can then be used to produce monoclonal antibodies.
Materialsatsen enligt uppfinningen omfattar minst tre behållare, varav en behållare innehåller lymfo- kiner som aktiv beståndsdel, en behållare innehåller lyso- somotropt agens, lysosomotropa derivat därav eller lysosomotropa substanser syntetiserade utifrån sådant agens som aktiv beståndsdel och en behållare innehåller polyklonal aktivator som aktiv beståndsdel. Material- satsen innehåller även olika engångsmaterial för under- lättande av reagensens påverkan på cellpopulationerna, liksom en beskrivning av hur den skall användas.The kit according to the invention comprises at least three containers, of which one container contains lymphokines as active ingredient, one container contains lysosomotropic agent, lysosomotropic derivatives thereof or lysosomotropic substances synthesized from such agent as active ingredient and one container contains polyclonal activator as active ingredient. The kit also contains various disposable materials to facilitate the effect of the reagent on the cell populations, as well as a description of how it is to be used.
Uppfinningen beskrivs närmare i följande utförings- exempel. 10 15 20 25 30 35 461 985 Exempel 1 læmuaiseria9_@eê_ëz@9§ëer9eaë§_§§§i9§n_9tën_§i11§§&§ ëy_e9lyë19a§l_§ë§¿y§§9: Musmjältceller (10 X 106 i DMEM med 10% fetalt kalvserum (FCS) (D10) behandlades med 1eucin-1eucin-O-metylester, 25 pM, i 15 min i celler/ml) suspenderade rumstemperatur. Cellerna tvättades 2-3 gånger i DMEM med 2% FCS (D2). Därefter utsattes de för en in vitro immunisering med det tymusberoende antigenet conalbumin, 1 ug/ml, som immunogen. Kulturen innehöll också MLC (supernatant från mixed lymphocyte culture) och super- natant från stimulerade EL-4 celler (Glad, C., Wenner- ström, G. och Fredlund, B.-M. i IN VITRO IMMUNISATION IN HYBRIDOMA TECHNOLOGY (Borrebaeck, C.A.K. Ed.) (1987), sid 105-113, Elsevier Science Publishers). Efter 5,dygns immunisering fuserades cellerna med myeloma celler från cellinjen Sp2/0. Efter 12-14 dagar testades de växande hybridomen med avseende på produktion av anti- genspecifika antikroppar respektive produktion av antikroppar av IgG-subklass.The invention is described in more detail in the following exemplary embodiments. 10 15 20 25 30 35 461 985 Example 1 læmuaiseria9_ @ eê_ëz @ 9§ëer9eaë§_§§§i9§n_9tën_§i11§§ & § ëy_e9lyë19a§l_§ë§¿y§§9: Musmjältceller (10 X 106 i DMEM with 10% fetal calf serum (FCS) (D10) was treated with 1eucine-1eucine-O-methyl ester, 25 pM, for 15 min in cells / ml) suspended room temperature. The cells were washed 2-3 times in DMEM with 2% FCS (D2). They were then subjected to an in vitro immunization with the thymus-dependent antigen conalbumin, 1 μg / ml, as immunogen. The culture also contained MLC (supernatant from mixed lymphocyte culture) and supernatant from stimulated EL-4 cells (Glad, C., Wennerström, G. and Fredlund, B.-M. in IN VITRO IMMUNIZATION IN HYBRIDOMA TECHNOLOGY (Borrebaeck , CAK Ed.) (1987), pp. 105-113, Elsevier Science Publishers). After 5 days of immunization, the cells were fused with myeloma cells from the Sp2 / 0 cell line. After 12-14 days, the growing hybridomas were tested for the production of antigen-specific antibodies and the production of IgG subclass antibodies, respectively.
Icke leucin-leucin-O-metyl-behandlade celler användes som kontroll.Non-leucine-leucine-O-methyl-treated cells were used as a control.
Resultaten framgår av tabell 1.The results are shown in Table 1.
Tabell 1 Celler % antigen-positiva % IgG-producerande hybridom hybridom av antigen- positiva hybridom obehandlade musmjältceller 5,3 14,3 1eu-leufQ-met- behandlade musmjältceller 5,3 42,9 Exempel 2 šmæ2§i§e§in9_meë_Ez@2§äer9eaëe_§e§i9sa_me§_§i1l§e§§ ë!_e91zkl9§§1_§k§i2§29r Musmjältceller behandlades såsom i exempel 1 med leucin-1eucin-0~mety1ester. Vid den efterföljande 461 10 15 20 25 30 35 985 6 immuniseringen användes conalbumin som immunogen (1 pg/ml) med tillsats av pokeweed mitogen (PWM) som polyklonal aktivator i en slutlig koncentration av 0,l%. Immuniseringen fick pågå i 5 dygn, varefter cellerna fuserades såsom i exempel l.Table 1 Cells% antigen-positive% IgG-producing hybridoma hybridoma of antigen-positive hybridoma untreated mouse spleen cells 5.3 14.3 1eu-leufQ-met-treated mouse spleen cells 5.3 42.9 Example 2 šmæ2§i§e§in9_meë_Ez @ 2§äer9eaëe_§e§i9sa_me§_§i1l§e§§ ë! _E91zkl9§§1_§k§i2§29r Mouse spleen cells were treated as in Example 1 with leucine-1eucine-0-methyl ester. In the subsequent immunization, conalbumin was used as the immunogen (1 pg / ml) with the addition of pokeweed mitogen (PWM) as the polyclonal activator at a final concentration of 0.1%. The immunization was allowed to proceed for 5 days, after which the cells were fused as in Example 1.
Celler som ej behandlats med leucin-leucin-O- -metyl eller PWM användes som kontroll.Cells not treated with leucine-leucine-O- -methyl or PWM were used as controls.
Resultaten framgår av tabell 2.The results are shown in Table 2.
Tabell 2 Celler % antigen-positiva % IgG-producerande hybridom hybridom av antigen- positiva hybridom obehandlade musmjältceller 5,3 14,3 leu-leu-O-met- och PWM-behandlade musmjältceller 31,9 62,4 Exempel 3 ___________ ______ _________________ ________________ §!_29lyël92al_§ë§¿2§E9z Musmjältceller behandlades såsom i exempel l med leucin-leucin-O-metylester. Vid den efterföljande immuniseringen användes det tymusoberoende antigenet dextran, l pg/ml. Immuniseringen fick pågå i 5 dygn, varefter cellerna fuserades såsom i exempel 1.Table 2 Cells% antigen-positive% IgG-producing hybridoma hybridoma of antigen-positive hybridoma untreated mouse spleen cells 5.3 14.3 leu-leu-O-met and PWM-treated mouse spleen cells 31.9 62.4 Example 3 ___________ ______ _________________ ________________ §_29lyël92al_§ë§¿2§E9z Mouse spleen cells were treated as in Example 1 with leucine-leucine O-methyl ester. In the subsequent immunization, the thymus-independent antigen dextran, 1 pg / ml, was used. The immunization was allowed to proceed for 5 days, after which the cells were fused as in Example 1.
Icke leucin-1eucin-0-metylbehandlade celler an-_ vändes som kontroll.Non-leucine-1eucine-O-methyltreated cells were used as a control.
Resultaten framgår av tabell 3.The results are shown in Table 3.
Tabell 3 Celler % antigen-positiva % IgG-producerande hybridom hybridom av antigen- positiva hybridom obehandlade musmjältceller 3,5 0 leu-leu-O-met- behandlade musmjältceller 4,5 0 10 15 20 25 30 461 985 Exemgel 4 læmuniss§i§¶_@së_§z@9§9ës:9s§ës_맧i9sa_@së_ëillästs §y_p9lzäl9n§l_ëë§iyë§9: Försöket enligt exempel 2 upprepades, men som immunogen användes det tymusoberoende antigenet dextran, l pg/ml, med tillsats av pokeweed mitogen (PWM) som polyklonal aktivator.Table 3 Cells% antigen-positive% IgG-producing hybridoma hybridoma of antigen-positive hybridoma untreated mouse spleen cells 3.5 0 leu-leu-O-met-treated mouse spleen cells 4.5 0 10 15 20 25 30 461 985 Exemgel 4 læmuniss§i §¶_ @ së_§z @ 9§9ës: 9s§ës_맧i9sa_ @ së_ëillästs §y_p9lzäl9n§l_ëë§iyë§9: The experiment according to example 2 was repeated, but as an immunogen the thymus-independent antigen dextran, 1 pg / ml, was used with addition of pokeweed mitogen (PWM) as polyclonal activator.
Celler som ej behandlats med leucin-leucin-O-metyl eller PWM användes som kontroll.Cells not treated with leucine-leucine-O-methyl or PWM were used as controls.
Resultaten framgår av tabell 4.The results are shown in Table 4.
Tabell 4 Celler % antigen-positiva % IgG-producerande hybridom hybridom av antigen- positiva hybridom obehandlade musmjältceller 3,5 0 leu-leu-O-met- och PWM-behandlade musmjältceller 27,7 10,6 Av de ovan beskrivna försöken framgår det att man erhåller en ökning av både utbytet av antigenposi- tiva hybridom och av andelen IgG-producerande hybridom av de antigenpositiva hybridomen då man använder en kombination av antingen ett tymusberoende eller ett tymusoberoende antigen och en polyklonal aktivator, vid jämförelse mellan obehandlade mjältceller och leu-leu-O-met-behandlade och PWM-behandlade musmjält- celler.Table 4 Cells% antigen-positive% IgG-producing hybridoma hybridoma of antigen-positive hybridoma untreated mouse spleen cells 3.5 leu-leu-O-met and PWM-treated mouse spleen cells 27.7 10.6 From the experiments described above it appears that obtaining an increase in both the yield of antigen-positive hybridomas and in the proportion of IgG-producing hybridomas of the antigen-positive hybridomas when using a combination of either a thymus-dependent or a thymus-independent antigen and a polyclonal activator, when comparing untreated spleen cells and leu leu-O-met-treated and PWM-treated mouse spleen cells.
Claims (8)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8803208A SE461985B (en) | 1988-09-13 | 1988-09-13 | IN VITRO IMMUNIZATION OF Lymphocyte-containing CELL POPULATIONS AND MATERIAL KIT |
| PCT/SE1989/000486 WO1990002795A1 (en) | 1988-09-13 | 1989-09-12 | In vitro immunisation of lymphocyte-containing cell populations and kit therefor |
| AU42069/89A AU4206989A (en) | 1988-09-13 | 1989-09-12 | In vitro immunisation of lymphocyte-containing cell populations and kit therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8803208A SE461985B (en) | 1988-09-13 | 1988-09-13 | IN VITRO IMMUNIZATION OF Lymphocyte-containing CELL POPULATIONS AND MATERIAL KIT |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| SE8803208D0 SE8803208D0 (en) | 1988-09-13 |
| SE8803208L SE8803208L (en) | 1990-03-14 |
| SE461985B true SE461985B (en) | 1990-04-23 |
Family
ID=20373301
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8803208A SE461985B (en) | 1988-09-13 | 1988-09-13 | IN VITRO IMMUNIZATION OF Lymphocyte-containing CELL POPULATIONS AND MATERIAL KIT |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU4206989A (en) |
| SE (1) | SE461985B (en) |
| WO (1) | WO1990002795A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0460065T3 (en) * | 1989-02-21 | 1994-09-26 | Terumo Corp | Method for inducing CD4 lymphocyte proliferation |
| HUT62803A (en) * | 1990-05-22 | 1993-06-28 | Univ California | Process for producing antigen-specific, high affinity human monoclonal antibody |
| JP3150991B2 (en) * | 1991-04-10 | 2001-03-26 | 協和醗酵工業株式会社 | Hybridoma production method |
| CA2770737C (en) | 2009-08-13 | 2020-05-12 | Crucell Holland B.V. | Antibodies against human respiratory syncytial virus (rsv) and methods of use |
| NZ703035A (en) | 2010-07-09 | 2016-06-24 | Crucell Holland Bv | Anti-human respiratory syncytial virus (rsv) antibodies and methods of use |
| US11123372B2 (en) | 2016-07-29 | 2021-09-21 | Prokidney | Bioactive renal cells for the treatment of chronic kidney disease |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4716111A (en) * | 1982-08-11 | 1987-12-29 | Trustees Of Boston University | Process for producing human antibodies |
| SE459008B (en) * | 1986-09-04 | 1989-05-29 | Bioinvent Int Ab | MAKE PRODUCING HUMAN MONOCLONAL ANTIBODIES |
-
1988
- 1988-09-13 SE SE8803208A patent/SE461985B/en not_active IP Right Cessation
-
1989
- 1989-09-12 WO PCT/SE1989/000486 patent/WO1990002795A1/en unknown
- 1989-09-12 AU AU42069/89A patent/AU4206989A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| SE8803208L (en) | 1990-03-14 |
| WO1990002795A1 (en) | 1990-03-22 |
| AU4206989A (en) | 1990-04-02 |
| SE8803208D0 (en) | 1988-09-13 |
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