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| 2. |
- Asp, Michaela, et al.
(författare)
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Spatial detection of fetal marker genes expressed at low level in adult human heart tissue
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure is a major health problem linked to poor quality of life and high mortality rates. Hence, novel biomarkers, such as fetal marker genes with low expression levels, could potentially differentiate disease states in order to improve therapy. In many studies on heart failure, cardiac biopsies have been analyzed as uniform pieces of tissue with bulk techniques, but this homogenization approach can mask medically relevant phenotypes occurring only in isolated parts of the tissue. This study examines such spatial variations within and between regions of cardiac biopsies. In contrast to standard RNA sequencing, this approach provides a spatially resolved transcriptome- and tissue-wide perspective of the adult human heart, and enables detection of fetal marker genes expressed by minor subpopulations of cells within the tissue. Analysis of patients with heart failure, with preserved ejection fraction, demonstrated spatially divergent expression of fetal genes in cardiac biopsies.
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| 3. |
- Corbascio, Matthias, et al.
(författare)
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Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.
- 2002
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Ingår i: Transplantation. - 1534-6080. ; 74:1, s. 35-41
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Blockade of CD40 ligand (CD40L; CD154, gp39) is a potential treatment for autoimmune disease and allograft rejection. However, CD40L-/- mice are capable of mobilizing cellular immune responses to viral, parasitic, and intracellular bacterial infections as well as rejecting skin grafts with nearly the same efficiency as wild-type mice. CD40L-deficient mice (CD40L-/-) or wild-type mice treated with anti-CD40L develop chronic vasculopathy only 8 weeks after allogeneic heart transplantation. To overcome CD40L-independent immune responses, we used anti-lymphocyte function-associated antigen monoclonal antibody (LFA)-1, which has previously been shown to inhibit CD8+ immune responses. METHODS: We conducted mixed lymphocyte reactions, cytotoxicity assays, skin transplantation, and vascularized heterotopic heart transplantation in wild-type B6 and CD40L-deficient mice in the presence and absence of anti-LFA-1 to study the effects of anti-LFA-1 in the absence of CD40L signaling. RESULTS: Anti-LFA-1 inhibited proliferation of naïve CD40L-/- mixed leukocyte reactions and the lysis of donor targets by CD40L-/- cytotoxic T lymphocytes. Anti-LFA-1-treated CD40L-/- mice that received fully MHC-mismatched skin grafts showed significant prolongation of graft survival, with a median survival time of 55 days (mean 66 days) compared with 13 and 21 days in wild-type and CD40L-/- controls, respectively. CD40L-/- mice that received fully MHC-mismatched vascularized heart transplants treated with four doses of 200 microg of anti-LFA-1 at the time of transplantation did not develop any signs of chronic vasculopathy 150 days after transplantation. CONCLUSION: These results indicate that anti-LFA-1 can complement CD40L inhibition in the prevention of undesirable immune responses.
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| 4. |
- Corbascio, Matthias, et al.
(författare)
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CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely.
- 2002
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Ingår i: Transplant Immunology. - 1878-5492. ; 10:1, s. 55-61
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Tidskriftsartikel (refereegranskat)abstract
- CTLA4Ig and anti-LFA-1 are members of a new generation of immunomodulatory drugs which inhibit important signaling pathways in T cell activation. Both substances target molecules which have pivitol functions in the activation of CD4+ and CD8+ T cells and have been theorized to have an interdependent relationship. These drugs have been used independently in various treatment regimens and have shown great promise in prolonging the survival of allografts. In order to test whether these substances have synergistic or potentiating effects when combined, we performed mixed lymphocyte reactions, skin transplantation and vascularised heterotopic heart transplantation in the Balb/c (H-2(d)) to C3H/HeJ (H-2(k)) strain combination. When anti-LFA-1 and CTLA4Ig were combined at low doses, there was a substantial inhibition of lymphocyte proliferation. When each drug was used as a mono-therapy in skin graft recipients, there was no significant effect on median graft survival (anti-LFA-1, 15 days; CTLA4Ig, 16 days) when compared to untreated controls (13 days), whereas a combination of anti-LFA-1 and CTLA4Ig extended graft survival significantly to 32 days. Untreated vascularised heart grafts rejected at a median of 8 days, CTLA4Ig-treated mice rejected at a median time of 79 days and anti-LFA-1-treated mice rejected at 43 days (n = 9). When CTLA4Ig and anti-LFA-1 were combined, all animals had functioning heart grafts at 100 days after transplantation. Histological analysis of combined-therapy hearts showed no signs or only minor changes associated with chronic rejection. In conclusion, these results indicate a synergistic effect of combining anti-LFA-1 with CTLA4Ig in inhibiting lymphocyte proliferation and prolonging the survival of fully MHC-mismatched allografts.
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| 5. |
- Corbascio, Matthias
(författare)
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Induction of operational tolerance to allografts and xenografts
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inhibition of the costimulatory molecules B7 and CD40L with CTLA4Ig and anti-CD40L administered only during the first week after transplantation induces indefinite survival of allo- and xenogeneic heart transplants and significantly prolongs skin grafts in C3H mice. However, this treatment protocol is not as effective in C57BL/6 mice which reject skin transplants with nearly the same median survival time as untreated controls. This has been shown to be due to the ability of CD8+ T cells to be activated autonomously of B7 or CD40L costimulation. LFA-1 is an important signaling molecule for CD8+ T cell function and we therefore hypothesized that its inhibition may compliment B7 and CD40L blockade and induce indefinite survival of transplants in mice. Anti-LFA-1 combined with CTLA4Ig induced indefinite survival of heart transplants after one week of treatment. Anti-LFA-1 also prevented immune responses and chronic vasculopathy in CD40L -/- mice. When CTLA4Ig was combined with anti-LFA-1 and given to CD40L -/- mice, dopaminergic porcine xenografts were accepted without any signs of rejection. The combination of anti-CD40L, CTLA4Ig and anti-LFA-1 induced permanent acceptance of dopaminergic porcine grafts in wild-type C57BL/6 mice. Surprisingly these recipients could be induced to rejected their grafts if challenged with glia cells of donor origin indicating that regulatory T cells maybe involved in the acceptance of these transplants. In order to ascertain the importance of regulatory T cells, IL-10 deficient mice were transplanted with allogeneic heart transplants and treated with costimulation blockade. A majority of these hearts stopped beating two days after transplantation succumbing to a massive neutrophilic infiltrate resembling myocardial infarction. The remaining hearts were rejected with in 50 days after transplantation. These results indicate that anti-LFA-1 can compliment CTLA4Ig and anti-CD40L in the induction of operational tolerance and that this state is facilitated by IL-10 and indirectly regulatory T cells.
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| 6. |
- Das, Sarbashis, et al.
(författare)
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Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure affects 2-3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics would show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction >= 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group.
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| 7. |
- Frisk, Christoffer, et al.
(författare)
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Cardiac biopsies reveal differences in transcriptomics between left and right ventricle in patients with or without diagnostic signs of heart failure
- 2024
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- New or mild heart failure (HF) is mainly caused by left ventricular dysfunction. We hypothesised that gene expression differ between the left (LV) and right ventricle (RV) and secondly by type of LV dysfunction. We compared gene expression through myocardial biopsies from LV and RV of patients undergoing elective coronary bypass surgery (CABG). Patients were categorised based on LV ejection fraction (EF), diastolic function and NT-proBNP into pEF (preserved; LVEF ≥ 45%), rEF (reduced; LVEF < 45%) or normal LV function. Principal component analysis of gene expression displayed two clusters corresponding to LV and RV. Up-regulated genes in LV included natriuretic peptides NPPA and NPPB, transcription factors/coactivators STAT4 and VGLL2, ion channel related HCN2 and LRRC38 associated with cardiac muscle contraction, cytoskeleton, and cellular component movement. Patients with pEF phenotype versus normal differed in gene expression predominantly in LV, supporting that diastolic dysfunction and structural changes reflect early LV disease in pEF. DKK2 was overexpressed in LV of HFpEF phenotype, potentially leading to lower expression levels of β-catenin, α-SMA (smooth muscle actin), and enhanced apoptosis, and could be a possible factor in the development of HFpEF. CXCL14 was down-regulated in both pEF and rEF, and may play a role to promote development of HF.
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| 8. |
- Fux, Thomas, et al.
(författare)
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Synthetic tracheal grafts seeded with bone marrow cells fail to generate functional tracheae : First long-term follow-up study
- 2020
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : MOSBY-ELSEVIER. - 0022-5223 .- 1097-685X. ; 159:6, s. 2525-2537.e23
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Synthetic tracheal grafts seeded with autologous bone marrow-mononuclear cells (BM-MNCs) have been described as becoming living and functional grafts representing a promising option for tracheal replacement for pathologies unamenable by segmental resection or autologous repair. This study aimed to present the first long-term follow-up of these procedures in humans.Methods: We retrospectively analyzed 3 patients who received synthetic tracheal grafts seeded with BM-MNCs implanted.Results: Patient 1 was a 37-year-old man with mucoepidermoid carcinoma, the first-ever human to receive a synthetic tracheal graft seeded with BM-MNCs. Patient 2 was a 30-year-old man with adenoid cystic carcinoma, and patient 3 was a 22-year-old woman with an iatrogenic tracheal injury. All patients developed graft-related complications necessitating multiple surgical reinterventions. Patient 1 was hospitalized for 8 months before dying from respiratory failure secondary to graft dehiscence 32 months after implantation. Patient 2 died 3.5 months after implantation from undisclosed causes. Patient 3 received a second synthetic tracheal graft after 11 months and an allogeneic trachea and lung transplantation 45 months after the primary implantation. Patient 3 underwent 191 surgical interventions after the primary implantation and spent 55 months in the intensive care unit before dying from airway bleeding. All patients' bronchoscopic, histologic, and radiologic investigations demonstrated graft-associated complications, including anastomotic fistulae and obstructive granulation tissue, without graft vascularization, mucosal lining, or integration into adjacent tissues.Conclusions: Synthetic tracheal grafts seeded with BM-MNCs do not become living functional tracheal grafts and lead to debilitating complications and death.
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| 9. |
- Grinnemo, Karl-Henrik, et al.
(författare)
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Costimulation blockade induces tolerance to HESC transplanted to the testis and induces regulatory T-cells to HESC transplanted into the heart
- 2008
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 26:7, s. 1850-1857
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Tidskriftsartikel (refereegranskat)abstract
- In order to study the ability of costimulation blockade to induce tolerance to human embryonic stem cells (HESC), severe combined immunodeficient (SCID), and immunocompetent C57BL/6 mice treated with costimulation blockade received intratesticular and intramyocardial HESC transplants. All SCID mice with intratesticular HESC transplants developed teratoma. When SCID mice were transplanted intramyocardially, only two of five mice developed teratoma-like tumors. C57BL/6 mice transplanted intratesticularly and treated with costimulation blockade all developed teratoma and were surrounded by CD4(+)CD25(+)Foxp3(+) T-cells, while isotype control treated recipients rejected their grafts. Most C57BL/6 mice transplanted intramyocardially and treated with costimulation blockade demonstrated lymphocytic infiltrates 1 month after transplantation, whereas one maintained its graft. Isolation of regulatory T-cells from intramyocardial transplanted recipients treated with costimulation blockade demonstrated specificity toward undifferentiated HESC and down-regulated naive T-cell activation toward HESC. These results demonstrate that costimulation blockade is sufficiently robust to induce tolerance to HESC in the immune-privileged environment of the testis. HESC specific regulatory T-cells developed to HESC transplanted to the heart and the success of transplantation was similar to that seen in SCID mice.
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