Survival of transplanted neural stem/progenitor cells (NSPC) is limited after spinal cord injury (SCI). This thesis tested whether ephrin-B3 could enhance the survival of spinal cord derived NSPC because ephrin-B3 enhanced the survival of endogenous NSPC in the mouse brain. Preclustered ephrin-B3-Fc was tested, and preclustered Fc fragments and phosphate-buffered saline (PBS) were used as controls. This study showed that spinal cord derived NSPC and normal and injured rat spinal cord expressed EphA4 receptors. In culture, ephrin-B3-Fc increased the survival of NSPC at 1µg/mL (p<0.05), but Fc fragments reduced NSPC survival dose-dependently. In the injured spinal cord, infusion of ephrin-B3-Fc increased the proliferation of endogenous ependymal cells compared with infusion of PBS (p<0.05). However, in the injured cord, infusion of either ephrin-B3-Fc or Fc fragments caused a 20-fold reduction in the survival of transplanted NSPC (p<0.001). Thus, after SCI, ephrin-B3-Fc and Fc fragments are toxic to transplanted NSPC.

Survival of transplanted neural stem/progenitor cells (NSPC) is limited after spinal cord injury (SCI). This thesis tested whether ephrin-B3 could enhance the survival of spinal cord derived NSPC because ephrin-B3 enhanced the survival of endogenous NSPC in the mouse brain. Preclustered ephrin-B3-Fc was tested, and preclustered Fc fragments and phosphate-buffered saline (PBS) were used as controls. This study showed that spinal cord derived NSPC and normal and injured rat spinal cord expressed EphA4 receptors. In culture, ephrin-B3-Fc increased the survival of NSPC at 1µg/mL (p<0.05), but Fc fragments reduced NSPC survival dose-dependently. In the injured spinal cord, infusion of ephrin-B3-Fc increased the proliferation of endogenous ependymal cells compared with infusion of PBS (p<0.05). However, in the injured cord, infusion of either ephrin-B3-Fc or Fc fragments caused a 20-fold reduction in the survival of transplanted NSPC (p<0.001). Thus, after SCI, ephrin-B3-Fc and Fc fragments are toxic to transplanted NSPC.

With over 50,000 deaths and 80,000 disorders annually in the United States resulting from traumatic brain injury (TBI), there is a demand for improved therapeutic strategies. Cell transplantation offers the potential to treat TBI by targeting multiple mechanisms in a sustained fashion. However, efforts are needed to improve survival and integration of transplanted cells, and ultimately enhance functional recovery. Using tissue engineering strategies, we aimed to mimic key aspects of fetal tissue grafts by combining neural stem cells with a fibronectin or laminin based scaffold that could be delivered to the injured brain in a minimally invasive fashion. We found that the incorporation of extracellular matrix proteins into a cell transplantation paradigm led to improved donor cell survival and restored cognitive ability for treated animals. To begin to examine how fibronectin and laminin mediate these improvements, we first examined the endogenous role of these two proteins in the injured brain. Using a clinically-relevant model of TBI, we found both proteins are increased in the injured brain at acute time points. The spatial localization of fibronectin and laminin with specific support cells in the brain suggests a role for these proteins in repair, warranting further investigation. Using conditional plasma fibronectin knockout animals, we found that fibronectin is neuroprotective to the traumatically injured brain. Specifically, injured fibronectin knockout animals had more severe motor and cognitive deficits, increased cell death, and decreased retention of phagocytic cells compared to injured wild type animals. Thus, we have identified novel therapeutic treatments for TBI which utilize tissue engineered transplants and/or exploit endogenous repair mechanisms for fibronectin.

Aufgrund der verfügbaren Literatur und Daten ist nicht erwiesen, dass eine prophylaktische Thrombozytentransfusion nach myeloablativer Chemotherapie notwendig oder für den Patienten vorteilhaft ist. Die im Verlauf der Jahre immer weiter gesenkten Schwellenwerte zur prophylaktischen Thrombozytentransfusion legten nahe, die Möglichkeit zu überprüfen, auf eine prophylaktische Substitution ganz zu verzichten und nur im Falle relevanter Blutungen zu transfundieren. Mit der hier ausgewerteten Studie liegen erstmals Daten aus einer multizentrischen, prospektiv randomisierten Studie zum Vergleich einer prophylaktischen mit einer therapeutischen Transfusionsstrategie für Thrombozyten nach autologer Stammzelltransplantation vor: es wurde eine prophylaktische Thrombozytentransfusion bei Thrombozytenwerten ≤ 10/nl mit einer neuen Transfusionsstrategie (Substitution nur bei relevanter Blutung oder definierten Risikosituationen) verglichen. Mit der experimentellen, therapeutischen Transfusionsstrategie für Thrombozyten kann eine Reduktion der Thrombozytentransfusionen um ca. 50% im Vergleich zu dem etablierten prophylaktischen Transfusionsregime erreicht werden: bei den hier untersuchten 92 Patienten wurden im experimentellen Arm für 47 Patienten nur 37 Thrombozytenkonzentrate benötigt, für die 45 prophylaktisch behandelten Patienten wurden insgesamt 71 Thrombozytenkonzentrate verbraucht. Die experimentelle therapeutische Transfusionsstrategie für Thrombozyten führte zu keiner statistisch signifikanten Zunahme von Blutungskomplikationen; auch bei der Anzahl der benötigten Erythrozytentransfusionen gab es keine signifikanten Unterschiede; Nebenwirkungen der Transfusionen, Dauer der Thrombopenie und Anzahl der Tage im Krankenhaus waren ebenso nicht signifikant unterschiedlich. Das Risiko, während der Beobachtungszeit (Chemotherapie und autologe Stammzelltransplantation bis zur Regeneration der Thrombozytenwerte), eine Blutung zu erleiden, lag insgesamt bei 14.1%; im experimentellen Arm lag das Risiko bei 19.2%, bei den prophylaktisch substituierten Patienten bei 8.9%; dieser Unterschied war statistisch nicht signifikant, ohnehin traten bei den beobachteten Patienten nur milde, klinisch wenig bedeutsame Blutungen des WHO – Schweregrades &amp;lt; 3 auf, es kam zu keinen blutungsassoziierten Todesfällen Bei klinisch stabilen Patienten und sorgfältiger Überwachung ist ein therapeutisches Transfusionsregime für Thrombozyten nach autologer Stammzelltransplantation praktikabel und sicher anwendbar, die Sicherheit dieses Vorgehens bei Patienten nach autologer Stammzelltransplantation wird mit der vorliegenden randomisierten Studie belegt. Eine therapeutische Thrombozytentransfusionsstrategie ist vermutlich bei einer Vielzahl weiterer hämato-onkologischer Patienten bzw. Krankheitsbilder ausreichend und kann unter signifikanter Einsparung kostbarer Thrombozytenkonzentrate bedrohliche Blutungen ebenso aufhalten oder verhindern wie ein prophylaktisches Regime.

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Introduktion Autolog stamcellstransplantation är idag en vanlig behandling vid myelom och högmaligna lymfom hos patienter &lt;65 år utan omfattande komorbiditet. Behandlingen delas upp i fem faser: induktionsbehandling, stamcellsmobilisering, stamcellsskörd, konditionering med högdoscytostatika och stamcellsåtergivning/transplantation. Initialt behandlades alla patienter som genomgick autolog stamcellstransplantation inom slutenvården under den sista behandlingsfasen, det vill säga i samband med konditionering och stamcellsåtergivning. Sedan 1990-talet har man dock på många håll i världen övergått till poliklinisk vårdform för denna patientgrupp. Detta innebär att patienten genomgår stamcellstransplantationen inom slutenvården men efter detta behandlas som öppenvårdspatient med fasta återbesök på sin hemklinik under posttransplantfasen. Poliklinisk vårdform har visat sig vara en säker, uppskattad och kostnadseffektiv vårdform som inte medför större risker för patienten och som inte ökar mortalitet och/eller morbiditet i samband autolog stamcellstransplantation. Syfte Syftet med denna studie är att undersöka om det föreligger skillnad i grad av cytostatikarelaterat fördröjt illamående och kräkningar mellan patienter som vårdats polikliniskt jämfört med patienter som vårdats inneliggande på vårdavdelning efter autolog stamcellstransplantation. Metod Studiepopulationen utgörs av 91 patienter varav 33 vårdades polikliniskt och 58 vårdades inom slutenvården efter autolog stamcellstransplantation. Patienterna fyllde i en illamåendedagbok i samband med behandlingen varpå dessa analyserades utifrån variabler gällande cytostatikarelaterat fördröjt illamående och kräkningar. Resultat Resultatet visar att de polikliniserade patienterna mår generellt bättre än de icke- polikliniserade patienterna vad gäller cytostatikarelaterat fördröjt illamående och kräkningar. Sammanfattning Föreliggande studie indikerar ett positivt samband mellan poliklinisk vårdform och lägre incidens av cytostatikarelaterat fördröjt illamående och kräkningar hos patienter som genomgår autolog stamcellstransplantation. / Introduction Treatment for myeloma and lymphoma today typically involves autologous stem cell transplantation for patients &lt;65 years without coexisting comorbidity. The treatment consists of five stages: induction treatment, stem cell mobilisation, stem cell harvest, conditioning with high dose chemotherapy and stem cell rescue (transplantation). Historically all patients treated with autologous stem cell transplantation received treatment as inpatients but this practice has since the 1990ies, due to for instance financial reasons, gradually shifted into an outpatient approach to this line of care. Thus, for the patient the outpatient approach entails myeloablative conditioning and stem cell transplantation as inpatient followed by post transplant care as outpatient part of the home clinic’s outpatient program. Outpatient care following autologous stem cell transplantation has proven to be a safe, highly appreciated and cost effective method of care without any adverse effects on behalf of the patients with regards to clinical outcome, mortality and/or comorbidity. Objectives The aim of this study is to ascertain whether or not there is a difference in degree of chemotherapy-induced delayed nausea and vomiting between an outpatient population and an inpatient population following autologous stem cell transplantation. Methods A total of 91 patients, 33 of whom were included in an outpatient program while remaining 58 were treated as regular inpatients, participated in the study. Patients each day filled out a diary with regards to nausea and emesis during the entire treatment phase. Submitted data was then analysed concerning parameters related to chemotherapy-induced delayed nausea and vomiting. Results The result shows that the outpatient population suffers less in general than the inpatient population in terms of chemotherapy-induced delayed nausea and vomiting. Conclusion To conclude, this study suggests a positive correlation between outpatient care following autologous stem cell transplantation and a lower incidence of chemotherapy-induced delayed nausea and vomiting.

[Truncated abstract] Microenvironmental changes associated with apoptotic neural degeneration may instruct a proportion of newly transplanted donor cells to differentiate towards the fate of the deteriorating host cellular phenotype. In the work described in this thesis, this hypothesis was tested by inducing apoptotic retinal ganglion cell (RGC) death in neonatal and adult rats and mice, and then examining whether intravitreally grafted cells from a range of sources of donor neural tissue became incorporated into these selectively depleted retinae. Donor tissues were: a postnatal murine cerebellar-derived immortalised neural precursor cell line (C17.2); an adult rat hippocampal-derived clonal stem-like line (HCN/GFP); mouse embryonic day 14 (E14) primary dissociated retinal cells (Gt[ROSA]26); and adult mouse ciliary pigmented margin-derived primary neurospheres (Gt[ROSA]26). In neonates, rapid RGC death was induced by removal of the contralateral superior colliculus (SC), and in adults, delayed RGC death was induced by unilateral optic nerve (ON) transection. Some adult hosts received ON transection coupled with an autologous peripheral nerve (PN) graft. Donor cells were injected intravitreally 6-48 h after SC ablation (neonates) or 0, 5, 7 or 14 days after ON injury (adults). Cells were also injected into non-RGC depleted neonatal and adult retinae. At 4 or 8 weeks, transplanted cells were identified, quantified and their differentiation fate within host retinae was assessed. Transplanted male C17.2 cells were identified in host retinae using a Y-chromosome marker and in situ hybridisation, or by their expression of the lacZ reporter gene product Escherichia coli beta-galactosidase (beta-gal) using Xgal histochemistry or a beta-gal antibody. No C17.2 cells were identified in axotomised adult-injected eyes undergoing delayed RGC apoptosis (n = 16). Donor cells were, however, stably integrated within the retina in 29% (15/55) of mice that received C17.2 cell injections 24 h after neonatal SC ablation; 6-31% of surviving cells were found in the RGC layer (GCL). These NSC-like cells were also present in intact retinae, but on average there were fewer cells in GCL. In SC-ablated mice, most grafted cells did not express retinal-specific markers, although occasional donor cells in the GCL were immunopositive for beta-III tubulin (TUJ1), a protein highly iii expressed by, but not specific to, developing RGCs. Targeted rapid RGC depletion thus increased C17.2 cell incorporation into the GCL, but grafted C17.2 cells did not appear to differentiate into an RGC phenotype.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 6 uppsatser.