Graft viability and transfusion related complications in patients undergoing stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment strategy for patients with hematopoietic malignancies and inborn errors of metabolism or immunodeficiencies. A successful clinical outcome depends on many factors, such as underlying disease, the patients’ status, treatment protocol, donor, graft source and occurrence and severity of complications such as graft versus host disease (GVHD) and infections. The scope of this thesis is to achieve greater understanding of clinical effects and immunological mechanisms of blood group differences and cellular transfusion in patients undergoing HSCT. In addition we investigate the impact of cell graft quality. HSCT can be performed across the ABO blood group barrier but the impact of blood group incompatibility in HSCT is debated. In scientific paper I we analyzed the impact of blood group differences on graft failure (GF). This is a retrospective single center study including 224 patients who underwent myeloablative allogeneic HSCT with grafts from an unrelated donor in 1997-2003. Graft failure (GF) was seen in 6 patients (2.7%). Major ABO mismatch and HLA allele mismatch was significantly associated with GF in the multivariate analysis. In scientific paper II we retrospectively analyzed 310 patients receiving reduced intensity conditioning (RIC) HSCT in 1998-2011. We found no influence of ABO mismatch on overall clinical outcome. However, patients with an ABO mismatched graft required more blood transfusions. We then investigated antibody related complications post-HSCT. Autoimmune hemolytic anemia did not affect overall survival (OS) or transplant related mortality (TRM). Patients with ABO related antibody complications post-HSCT had inferior OS and more TRM. These studies imply that the role of ABO mismatches is not obvious. However, other factors of greater impact may override the effect of ABO donor-recipient differences thus obfuscating its influence. In scientific paper III we retrospectively investigated the impact of HSCT grafts with inferior quality on clinical outcome in 144 patients receiving peripheral blood stem cell grafts. Graft quality was measured as viability of a frozen/thawed control sample. Patients who received grafts with inferior quality developed acute GVHD more frequently and had higher TRM. Grafts with white blood cell count >300 x109/L had lower viability. In conclusion, graft quality influence clinical outcome after HSCT, hence, conditions for graft storage and handling need to be optimized. In patients that develop mucositis or breakthrough infections after HSCT, granulocyte transfusions (GCX) can be used. Scientific paper IV addresses GCX treatment in 85 patients between 1998 and 2014. GCX can be obtained from donors pretreated with steroids only (S-GCX) or steroids and G-CSF (GCSF-GCX). The overall response to GCX treatment was similar between S-GCX and GCSF-GCX but more complete responses were observed in the GCSF-GCX group. Patients who received GCX due to mucositis benefitted most from GCX whereas the effects of GCX in patients treated due to infection was not as clear. Adverse events (AE) were reported in 36 cases of which 6 were life-threatening or fatal pulmonary AEs. All severe AEs reported were seen in patients treated due to severe infection, further complicating the decision to use GCX treatment in these patients

Individualization of Hematopoietic Stem Cell Transplantation Using Alpha/Beta T-Cell Depletion

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of αβ T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The αβ T-cell depleted cell products were characterized by flow cytometry. The median log depletion of αβ T-cells was −4.3 and the median yield of γδ T-cells was 73.5%. The median CD34+ cell dose was 4.4 × 106/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of αβ T-cell depleted products as stem cell boosters with encouraging results

Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase-induced inflammation

Background Immunity decreases with age, which leads to reactivation of varicella zoster virus (VZV). In human subjects age-associated immune changes are usually measured in blood leukocytes; however, this might not reflect alterations in tissue-specific immunity. Objectives We used a VZV antigen challenge system in the skin to investigate changes in tissue-specific mechanisms involved in the decreased response to this virus during aging. Methods We assessed cutaneous immunity based on the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsy specimens taken from the challenge site in young (65 years) subjects. Results Old human subjects exhibited decreased erythema and induration, CD4+ and CD8+ T-cell infiltration, and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared with young subjects. This was associated with increased sterile inflammation in the skin in the same subjects related to p38 mitogen-activated protein kinase–related proinflammatory cytokine production (P < .0007). We inhibited systemic inflammation in old subjects by means of pretreatment with an oral small-molecule p38 mitogen-activated protein kinase inhibitor (Losmapimod; GlaxoSmithKline, Brentford, United Kingdom), which reduced both serum C-reactive protein levels and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge were increased significantly in the same subjects (P < .0003). Conclusion Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However, this can be reversed by inhibition of inflammatory cytokine production that can be used to promote vaccine efficacy and the treatment of infections and malignancy during aging

Processing unit resources in a distributed computing systems

The described program is designed for collecting, storing and processing data of distributed file system

"Varför har du gått vilse i en värld där jag inte släpps in?” : – En kvalitativ studie om barns erfarenheter av att växa upp med en förälder med psykisk ohälsa

Att vara barn till en förälder med psykisk ohälsa kan föranleda svårigheter och problematik. Denna studie syftar till att skapa förståelse för vilka upplevelser och erfarenheter barn till föräldrar med psykisk ohälsa har av sin uppväxt och barndom. Studiens analysmaterial består av fem självbiografier, samtliga skrivna av barn som växt upp med en förälder med psykisk ohälsa. Frågeställningarna behandlar hur relationen mellan barnet och föräldern beskrivs i berättelserna, hur förälderns psykiska ohälsa påverkar barnets egna mående och vilka skyddsfaktorer för barnet som återfinns i berättelserna. Teorivalet symbolisk interaktionism i kombination med den vetenskapliga utgångspunkten, hermeneutiken, bidrar med förståelse för hur barnen upplever sin situation utifrån berättelserna. Resultatet redogör fyra framträdande teman som hjälper läsaren att förstå barnens upplevda verklighet: hur den psykiska ohälsan yttrar sig, känslor, ombytta roller och skyddsfaktorer. Dessa nämnda teman återfanns i samtliga böcker i varierande utsträckning. Då samma teman och mönster återfanns i många av böckerna kunde generella slutsatser dras. Slutsatserna som dragits i denna studie har också stöd i tidigare forskning.

The impact of transportation time on apoptosis in allogeneic stem cell grafts and the clinical outcome in malignant patients with unrelated donors

Background: The quality of cells in peripheral blood stem cell (PBSC) grafts is important for allogeneic stem cell transplantation outcome. The viability of PBSC grafts may decrease during transportation time between donor and transplant center. We hypothesize that the graft viability based on apoptosis and necrosis in the graft may better reflect graft quality and clinical outcome. Methods: PBSC graft viability from unrelated donors was analyzed in 91 patients. Viable cells were defined as 7-aminoactinomycin D- and Annexin V-negative. The clinical outcome, including survival, transplantrelated mortality and graft-versus-host disease (GvHD), was correlated to graft viability. Results: Grafts transported for 1 day had a median viability of 86.4% (range 63.8 to 98.9%), and grafts transported for 2 days had median viability of 83.2% (range 52.8% to 96.2%) (P = .003). Grafts were divided into two groups based on the median graft viability of 85.1%. Patients who received low viability grafts had lower 1-year survival of 63.7% compared with 88.9% for those who received high viability grafts (P = .007). In the multivariate analysis, transplant-related mortality (TRM) was higher in the low viability group (P = .03), whereas overall survival was not significantly associated with graft viability. The incidence of acute GvHD grade II to IV, chronic GvHD and relapse risk remained comparable between the groups. Conclusion: Low graft viability was an independent predictor of 1-year survival and TRM after adjusting for multiple confounders. Better graft quality markers are important for the detection of clinically important variations in the stem cell graft. (c) 2022 International Society for Cell &amp; Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

Higher response rates in patients with severe chronic skin graft-versus-host disease treated with extracorporeal photopheresis

Introduction: Different forms of graft-versus-host disease (GVHD) remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The prognosis for steroid-refractory chronic GVHD (cGVHD) remains poor. Our aim was to evaluate extracorporeal photopheresis (ECP) treatment in cGVHD patients with different organ involvement to detect subgroups of patients with the best response. Material and methods: Thirty-four patients who underwent HSCT and developed moderate (n = 7) or severe (n = 27) steroid-refractory or steroid-dependent cGVHD treated with ECP were included in the analysis. A matched cGVHD control patient group untreated with ECP was collected for comparison. Results: Compared to the control group and the stable/progressive disease (SD/PD) patients, individuals with complete/partial remission have higher overall survival and lower transplant-related mortality. Furthermore, patients with complete and partial remission (CR/PR) had significantly higher levels of albumin and platelets after ECP treatment compared to patients with stable or progressive cGVHD (SD/PD). Corticosteroid treatment and other immunosuppressive agents could successfully be tapered in the CR/PR group compared to the SD/PD patients. In this study patients with skin cGVHD are those with the highest rate of CR/PR after ECP treatment. Conclusions: Our results suggest that ECP treatment is safe and effective for patients with predominantly skin, oral and liver cGVHD

Insights into the evolution of enzymatic specificity and catalysis: From Asgard archaea to human adenylate kinases

Enzymatic catalysis is critically dependent on selectivity, active site architecture, and dynamics. To contribute insights into the interplay of these properties, we established an approach with NMR, crystallography, and MD simulations focused on the ubiquitous phosphotransferase adenylate kinase (AK) isolated from Odinarchaeota (OdinAK). Odinarchaeota belongs to the Asgard archaeal phylum that is believed to be the closest known ancestor to eukaryotes. We show that OdinAK is a hyperthermophilic trimer that, contrary to other AK family members, can use all NTPs for its phosphorylation reaction. Crystallographic structures of OdinAK-NTP complexes revealed a universal NTP-binding motif, while $^{19}$F NMR experiments uncovered a conserved and rate-limiting dynamic signature. As a consequence of trimerization, the active site of OdinAK was found to be lacking a critical catalytic residue and is therefore considered to be “atypical.” On the basis of discovered relationships with human monomeric homologs, our findings are discussed in terms of evolution of enzymatic substrate specificity and cold adaptation