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Micro Environments Oft and B Lymphocytes MICRO ENVIRONMENTS OFT AND B LYMPHOCYTES A LIGHT- AND ELECTRONMICROSCOPIC STUDY PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE GENEESKUNDE AAN DE ERASMUS UNIVERSITEIT TE ROTTERDAM OP GEZAG VAN DE RECTOR MAGNIFICUS PROF. DR. B. LEIJNSE EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN DE OPENBARE VERDEDIGING ZAL PLAATS VINDEN OP WOENSDAG 30 MAART 1977 DES NAMIDDAGS TE 4.15 UUR PRECIES DOOR WILLEM VAN EWIJK geboren te Rheden PROMOTOR: PROF.DR.O. VOS CO-REFERENTEN: PROF. DR. H. GALJAARD DR. P. NIEUWENHUIS Dit proefschrift werd bewerkt binnen de vakgroep Celbiologie en Geneti<.:a van de Erasmus Universiteit te Rotterdam. Aan mijn ouders Aan Tilly VI Contents pag. Voorwoord Chapter 1 General introduction I 1.1 Pluripotent haemopoietic stem cells I 1.2 Haemopoietic microenvironments I 1.3 Differentiation of lymphoid cells 3 1.3.1 B cell differentiation 4 1.3.2 T cell differentiation 4 1.4 Humoral factors involved in haemopoiesis 6 1.4.1 Erythropoietin 6 1.4.2 Thrombopoietin 6 1.4.3 Colony stimulating factors 6 1.4.4 Humoral factors involved in lymphopoiesis 7 1.5 Purpose of investigation 8 Chapter 2 Architecture of spleen and lymph nodes 9 2 .I The spleen 9 2.1.1 Vascularization of the spleen 9 2.1.2 Haemopoietic compartments in the spleen 9 2.1.3 The white pulp, T and B cell compartments 11 2.2 Lymph nodes 12 Chapter 3 Discussion of the papers 15 3.1 Paper I 15 3.2 Paper II 17 3. 3 Paper III 19 3.4 Paper IV 21 3.5 Paper V 23 3.6 Paper VI 26 Summary 29 Samenvatting 33 References 37 Curriculum vitae VII Papers: Paper I White pulp compartments in the spleen of rats and mice. A light- and electronmicroscopic study of lymphoid and non-lymphoid cell types in T and B areas. A. J.P. Veerman and W. van Ewijk. Cell Tissue Res. 156, 417-441 (1975). Paper II Reconstitution of the thymus dependent area in the spleen oflethally irradiated mice. A light- and electronmicroscopic study of the T cell microenvironment. W. van Ewijk, J.H.M. Verzijden, Th. H. van der Kwast and S. W. M. Luijcx-Meijer. Cell Tissue Res. 149, 43-60 (1974). Paper III Migration of B lymphocytes in lymphoid organs of lethally irradia­ ted, thymocyte reconstituted mice. W. van Ewijk and Th. H. van der Kwast. Submitted for publication. Paper IV Cellular events during the primary immune response in the spleen. A fluorescence-, light- and electronmicroscopic study in germfree m1ce. W. van Ewijk, J. Razing, N.H.C. Brons and D. Klepper. Cell Tissue Res., in press. Paper V Scanning electron microscopy of homing and recirculating lympho­ cyte populations. W. van Ewijk, N.H. C. Brons and J. Razing. Cell. Immunol. 19, 245-261 (1975). Paper VI Cell surface labeling of mononuclear cells with antisera associated to turnip yellow mosaic virus or alphalpha mosaic virus particles. A freeze-etch study. W. van Ewijk and E. de Vries. Histochem. J. in press. VIII Voorwoord Gaame wil ik in dit voorwoord mijn dank betuigen aan allen die meegewerkt hebben aan het tot stand komen van dit proefschrift. In het bijzonder dank ik mijn promotor, Prof. Dr. 0. Vas, voor de mogelijkheden die hij mij geboden heeft om experimenteel onderzoek te verrichten, voor de vrijheid mij gegeven tijdens de keuze en opzet van het hier beschreven experimentele werk en voor de bijzonder stimulerende wijze waarop hij mij begeleid heeft tijdens het tot stand komen van dit proefschrift. Daarnaast wil ik de beide co-referenten noemen die mijn proefschrift op nauwgezette wijze hebben doorgenomen. Prof. Dr. H. Galjaard ben ik zeer erkentelijk voor zijn stimulerende invloed op mijn werk en zijn kritische houding ten opzichte van mijn publicaties en mijn proefschrift. Dr. P. Nieuwenhuis, beste Paul, jou bedank ik voor de wijze waarop jij mij in de afgelopenjaren begeleid hebt. Onze vele besprekingen over dit onderzoek, soms in Groningen, soms in Rotterdam en soms tijdens lange telefoongesprekken tussen Groningen en Rotterdam gaven mij energie om nieuwe experimenten op te zetten, resultaten af te ronden en deze tenslotte op te schrijven. Oak ben ik dank verschuldigd aan zij die direct bijgedragen hebben tot het hier beschreven experimentele werk, met name Suzanne Luijcx-Meijer, Rene Brons en Dick Klepper. Dank voor de eindeloze series dunne en ultradunne coupes welke vaak onder "trillerige" werkomstandigheden vervaardigd moes­ ten worden. Daamaast dank aan Jacques Verzijden, Thea van der Kwast en Egbert de Vries. Jullie hebben als student-assistent een zeer gewaardeerde bijdrage geleverd in het opzetten van de perfusie-fixatie techniek, de autoradiografie en de vries-ets techniek. Voorts wil ik diegenen noemen die dankzij hun technische bijdrage mij het werken mogelijk hebben gemaakt. Piet Hartwijk, Jan Ekas, Peter Lammerts en Anton Hoegee, jullie dank ik voor de constructie van het perfusie apparaat en het "drankorgel". Cor Bakker, van de afdeling elektronenmikroskopie van de Universiteit van Amsterdam ben ik zeer erkentelijk voor instructie en technische hulp tijdens ons scanning elektronenmikroskopisch onderzoek. Joop Bos en Cornelie Francken, mede dank zij jullie waren er goed verzorgde proefdieren, Mevrouw Godijn en Jopie Bolman zorgden altijd voor schoon glaswerk en, niet te vergekH, verse koffie tijdens het werk. Margot van Duuren en Rein Smid wil ik bedanken voor de snelle service tijdens bestellingen van materiaal. Dan wil ik allen noemen die mij in de afgelopen jaren met raad en daad terzijde hebben gestaan. Vooral dank aan Dr. 0. Brocades Zaalberg van het Medisch Biologisch Laboratorium TNO te Rijswijk, Prof. Dr. H.L. Lange­ voort van de afdeling histologie van de Vrije Universiteit te Amsterdam, Dr. E. Ch. M. Hoefsmit van de afdeling elektronenmikroskopie van de Vrije Universiteit te Amsterdam en Dr. W. Leene van het Jan Swammerdam Instituut, Universiteit van Amsterdam. Ook dank aan Jan Razing, Rob Benner, Rob Ploemacher, Wim van Muiswinkel en Anjo Veerman voor collegiale samenwerking en waardevolle discussies tijdens ons werk. En dan natuurlijk IX dank aan onze EM-unit (Rene, Han, Pim, Rob, Peter, Peter, Dick, Nol, Maud) voor het "sfeertje" wat het werken onder soms moeilijke omstandigheden zoveel gemakkelijker maakte. Marilyn Heukels-Dully, jij hebt vaak een zeer gewaardeerde bijdrage geleverd door het kritisch doomemen van de engelse tekst van manuscripten. Dan een bijzonder woord van dank voor de "fotografie" en voor het "sekretariaat". Joop Fengler en Tar van Os, jullie hebben telkens weer met zorg die eindeloze series foto's afgedrukt, dia's ingeraamd, haast-klussen geleverd (vandaag klaar, liever gisteren) en dat bovendien met een bijzonder positieve ins telling en een grate dosis humor. Hartelijk dank hiervoor! Leny Breteler, Inge Horssen- van der Kaai, Rita van den Hoek- Boucke, Thea van Drunen- van Rijn, Cecile van Vugt- van Vliet, en vooral Cary Clerkx, jullie typten brieven, voortgangsverslagen en steeds maar weer nieuwe versies van manuscripten. Voor jullie nauwgezetheid en snelle aflevering ben ik jullie zeer dankbaar. Jan J os en andere "spelers" dank ik voor de fijne samenwerking tijdens de voorbereidingen en uitvoering van drie cabaretprogramma's. Naast een onderlinge vaktechnische samenwerking zijn deze "sociale activiteiten" immers zo belangrijk voor bet goed functioneren van een afdeling. Tenslotte dank ik mijn ouders omdat zij mij in de gelegenheid stelden om biologie te studeren. Lieve Tilly, dank je wei, voor alles. Chapter 1 General Introduction 1.1 Pluripotent Haemopoietic Stem Cells Peripheral blood cells- erythrocytes, granulocytes, monocytes, thrombocy­ tes and lymphocytes-are the end products of a differentiation process which occurs in the bone marrow and, in rodents, also in the spleen. Normal haemopoietic tissue is a cell renewal system with an accurate balance between cell production originating from pluripotent haemopoietic stem cells and continuous cell loss. The important function of haemopoietic stem cells was emphasized by Till and McCulloch (1961) in bone marrow transplantation studies in mice. They noted that intravenous injection of small numbers of bone marrow cells into lethally irradiated syngeneic recipient mice caused the appearance of haemopoietic colonies in the spleen of the recipient mice. These colonies consisted either of erythroid, granuloid, megakaryocytic or mixed cell populations (Curry and Trentln, 1967). The technique used by Till and McCulloch is known as the "spleen colony assay" and has established two major qualities of haemopoietic stem cells: (I) they have the capacity of self replication (Trentin and Fahlberg, 1963; Curry et a!., 1967) and (2) they are pluripotent since they give rise to clones of different cell types of which the differentiated "end" cells recirculate in the blood (Till and McCulloch, 1961; Becker eta!., 1963; Till, 1976). In contrast to erythroid and myeloid colonies, lymphoid colonies were not detectable with the spleen colony assay; however, Ford et al. (1966), Micklem et a!. (1966), and Wu et a!. (1968) demonstrated with chromosome marker techniques that lymphoid cells were also derived from pluripotent haemopoietic stem cells. One of the major questions in cell biological investigations of haemopoiesis concerns the factors which determine the commitment and differentiation of pluripotent haemopoietic stem cells. At present it is generally accepted that two types of factors are involved in the regulation of haemopoiesis: (I) microenvironmental factors (see 1.2), and (2) humoral factors (see 1.4). 1.2 Haemopoietic microenvironments A haemopoietic microenvironment is defined as a special region in a haemopoietic organ which differs from adjacent areas and in which local conditions influence the proliferation and differentiation of immigrant - haemopoietic stem- cells (Metcalf and Moore, 1971). It is assumed that a microenvironment is created by stromal cells in haemopoietic organs (Curry and Trentin, 1967; Trentin, 1970). Convincing evidence that microenviron­ ments determine the differentiation pathway of haemopoietic stem cells came a.o. from the work of Curry eta!.
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