BB02 Improves Therapeutical Effectiveness Of Extracorporeal Photopheresis With 8-MOP In a Murine Model Of Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5416-5416
Author(s):  
David Garcia-Bernal ◽  
Miguel Blanquer ◽  
Jose Antonio del Rio ◽  
Enrique Correal ◽  
Maria del Carmen Algueró ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Lethal Dose ◽  
Therapeutic Effectiveness ◽  
Allogeneic Bone ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction Extracorporeal photopheresis (ECP) is a cell-based immunomodulatory therapy involving the separation of peripheral blood autologous mononuclear cells followed by ex-vivo administration of 8-methoxypsoralen (8-MOP) and UVA radiation before reinfusion. ECP is efficient for the treatment of multiple diseases mediated by unregulated T cell populations, such as cutaneous T cell lymphoma, autoinmune diseases or graft-versus-host disease (GVHD), the major complication after allogeneic bone marrow transplantation. Our aim in the present work was to compare the therapeutic effectiveness of 8-MOP with other two new compounds (BB01 and BB02) in a experimental murine model of GVHD. Methods Murine GVHD was induced after transplanting bone marrow cells and splenocytes from donor Balb/c mice into C57Bl6J recipients previously conditioned with a lethal dose of 10 Gy split into two doses of 5 Gy spaced 24 hours apart. To investigate the therapeutic effectiveness of ECP with either 8-MOP, BB01 or BB02, splenocytes from separate cohorts of C57Bl6J with GVHD were isolated 12 days after transplantation, incubated with the different compounds, irradiated with UVA light and injected intravenously once a week for four weeks. Survival after transplantation was monitored daily and clinical GVHD was graded using a previously described score analyzing weight loss, posture (hunching), activity, skin integrity and fur texture (Cooke et al, 1996). Mice of each group were evaluated and graded from 0 to 2 for each criterion, obtaining a clinical index by summation of the five criteria scores (maximum index=10). Results Mice treated weekly with BB02 showed a significant higher survival than those treated with 8-MOP (p=0,038), while BB01 had a similar effect to that of 8-MOP. Mice treated with either compound improved their clinical GVHD score compared to untreated mice group, being significantly lower with BB02 than with BB01 and 8-MOP (p=0,023). Conclusions BB02 was more efficient than 8-MOP in the reversal of murine GVHD, while BB01 showed the same therapeutic effectiveness than 8-MOP. Acknowledgments Work financed by the Spanish Ministry of Science and Innovation (Ref: BFU2010-19599) and the Spanish Net of Cell Therapy (TerCel) from Institute of Health Carlos III. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Molecular analysis of T-cell receptor repertoire in bone marrow transplant recipients: evidence for oligoclonal T-cell expansion in graft-versus-host disease lesions

Blood ◽  
1996 ◽  
Vol 87 (7) ◽  
pp. 3032-3044 ◽  
Author(s):  
X Liu ◽  
V Chesnokova ◽  
SJ Forman ◽  
DJ Diamond
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Supporting Evidence ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Beta 2

We have analyzed the T-cell receptor (TCR) V beta repertoire using polymerase chain reaction (PCR) in a cohort of eight patients receiving allogeneic bone marrow transplantation (BMT) from related and unrelated donors at the City of Hope. Results of PCR studies from graft-versus- host disease (GVHD) skin lesions show a bias in the usage of TCR V beta families, whereas examination of peripheral blood (PB) withdrawn at the same time did not reveal a similar phenomenon. In one such family, TCR V beta 2 is predominantly expressed in 7 of 7 biopsy specimens examined. V beta 2 TCR expression from these patients was analyzed more extensively using a combination of individual TCR gene cloning, followed by sequence analysis. We found evidence of oligoclonal expansion of single V beta 2-bearing TCRs in GVHD lesions, and in the PB of some patients after diagnosis of GVHD. In contrast, GVHD-negative biopsy samples showed no evidence for clonotypic TCR amplification. Sequence-specific TCR CDR3 region probes were derived from analysis of the predominant expressed TCR in GVHD lesions, and used to probe Southern blots of amplified V beta 2 TCR mRNA from PB and tissue from BMT recipients and their respective donors. In most cases the probes are highly specific in detecting TCR expression from GVHD lesions alone, although in several instances expression could be detected in PB after GVHD diagnosis. These data provide supporting evidence for the hypothesis that acute GVHD is associated with expansion of T-cell clones expressing antigen-specific TCRs that may contribute to the disease pathology.

scholarly journals HLA-target antigens and T-cell receptor diversity of activated T cells invading the skin during acute graft-versus-host disease

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2345-2353 ◽  
Author(s):  
J Gaschet ◽  
MA Trevino ◽  
M Cherel ◽  
R Vivien ◽  
A Garcia-Sahuquillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
T Cell Receptor ◽  
Graft Versus Host Disease ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
T Cell Clones ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Clones

To study the repertoire and specificity of T lymphocytes infiltrating skin lesions during graft-versus-host disease (GVHD), we performed an exhaustive molecular and functional analysis of 146 T-cell clones derived from the skin of three patients undergoing an acute GVHD after allogeneic bone marrow transplantation (BMT) from HLA-mismatched related donors. Analysis of T-cell receptor (TCR) rearrangement and TCR chain junctional sequences demonstrated the presence of 11 distinct clones among the 64 derived from patient UPN1, six among the 58 derived from patient UPN2, and seven among the 24 derived from patient UPN3. Three of the 11 T-cell clones from patient UPN1, and all clones from patients UPN2 and UPN3 reacted with mismatched HLA alleles between the bone-marrow donor and recipient. Moreover, both HLA class I (HLA-A2 and -B27) and class II (HLA DP101, DP401, DP1301, DQ8, and DR402) molecules were recognized during this early antihost response. Finally, both TCR alpha and beta chains turned out to be extremely diverse, even within populations of clones derived from the same patient and directed against the same HLA allele. Taken together, these results indicate that any HLA mismatch is potentially targeted during early GVHD, and that the T-cell response at the onset of GVHD is both oligoclonal and highly diversified.

scholarly journals Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3390-3397 ◽  
Author(s):  
Laurent Burnier ◽  
François Saller ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
Rocco Sugamele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

T-cell depletion of allogeneic bone marrow prevents acceleration of graft-versus-host disease induced by exogenous interleukin 2

1986 ◽  
Vol 103 (2) ◽  
pp. 476-480 ◽  
Author(s):  
Miroslav Malkovský ◽  
Malcolm K. Brenner ◽  
Ruth Hunt ◽  
Sohaila Rastan ◽  
Caroline Dore ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Interleukin 2 ◽  
Allogeneic Bone Marrow ◽  
Cell Depletion ◽  
Allogeneic Bone ◽  
T Cell Depletion ◽  
Host Disease ◽  
Graft Versus Host

CEACAM-1 Is Involved in Graft-Versus-Host-Disease in Murine Allogeneic Bone Marrow Transplantation Models.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 67-67
Author(s):  
Sydney X. Lu ◽  
Lucy Willis ◽  
Marsinay Smith ◽  
David Suh ◽  
Christopher King ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Small Bowel ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host

Abstract Carcinoembryonic antigen associated cell adhesion molecule 1 (CEACAM-1) belongs to a family of carcinoembryonic antigen-associated glycoproteins. It is expressed on leukocytes, endothelium, and epithelium. Microarray analysis showed that CEACAM-1 mRNA is increased in the small bowel during gut graft-versus-host-disease (GVHD) after allogeneic bone marrow transplantation (allo-BMT). Using CEACAM-1−/− mice as recipients or sources of donor bone marrow or T cells caused significantly worse GVHD mortality (p<0.05) compared to wildtype (WT) controls. Histopathological analysis of GVHD target organs from CEACAM-1−/− recipients of WT T cells or WT recipients of CEACAM-1−/− T cells revealed increased GVHD of the large bowel (p<0.05) but not liver or small bowel compared to WT control. Alloreactive splenic CD8 CEACAM-1−/− T cells from recipients with GVHD had increased levels of α4β7 integrin compared to WT controls. We also found increased numbers of small bowel intraepithelial lymphocytes and mesenteric lymph node cellularity in CEACAM-1−/− recipients of WT T cells and WT recipients of CEACAM-1−/− T cells, with a corresponding decrease of cellularity in peripheral lymph nodes and the liver. Adoptive transfer of CFSEhi CEACAM-1−/− T cells into WT hosts, or of WT T cells into CEACAM 1−/− hosts revealed more profound activation of T cells in CEACAM-1 deficient settings, shown by increased early CD25 expression and CD62L down-regulation on splenic CFSEdim alloreactive T cells. We found no significant differences in serum levels of TNF or IFNγ, T cell proliferation kinetics upon adoptive transfer, percentages of alloactivated CD4 or CD8 cells, intracellular levels of T-bet or IFNγ, CD8 T cell cytolytic efficiency, percentages of splenic regulatory T cells, or levels of T cell apoptosis in WT recipients of CEACAM-1−/− T cells or CEACAM-1−/− recipients of WT T cells with GVHD as compared with controls. Finally, irradiation of non-transplanted CEACAM-1−/− mice revealed increased radiation sensitivity, shown by earlier and greater lethality and increased small bowel crypt apoptosis, suggesting a role for CEACAM-1 in conditioning-related toxicity and subsequent GVHD amplification. We conclude that CEACAM-1 deficiency on donor T cells or transplant recipients results in increased gut and systemic GVHD due to increased T cell activation and elevated expression of the gut homing integrin α4β7. This suggests that the use of CEACAM-1 agonists could be a novel theraputic strategy for ameliorating acute intestinal and systemic graft-versus-host-disease.

scholarly journals OP0242 EFFECTS OF THE AUTOTAXIN INHIBITOR ZIRITAXESTAT ON SKIN AND LUNG FIBROSIS IN A MURINE GRAFT-VERSUS-HOST DISEASE MODEL OF SYSTEMIC SCLEROSIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 148.1-149
Author(s):  
Y. Zhang ◽  
L. Summa ◽  
B. Heckmann ◽  
J. H. W. Distler
Keyword(s):  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Graft Versus Host Disease ◽  
Murine Model ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Dermal Thickness ◽  
Disease Modifying

Background:There is an unmet medical need for new drugs to treat systemic sclerosis (SSc). Autotaxin (ATX) is a widely expressed enzyme that regulates diverse cellular processes, including proliferation, differentiation and migration, and has been implicated in the pathogenesis of SSc. Targeting ATX is a promising new strategy for treating SSc. The autotaxin inhibitor ziritaxestat (GLPG1690) is a potential first-in-class disease-modifying drug for SSc that has been shown to improve skin score in the Phase 2a NOVESA (NCT03798366) trial in patients with SSc.Objectives:To investigate the effects of ziritaxestat in a chronic graft-versus-host disease (cGvHD) murine model of SSc.Methods:Effects of ziritaxestat (10 or 30 mg/kg twice daily [bid]) on disease activity were assessed in a cGvHD murine model of SSc (allogeneic bone marrow transplantation [BMT] with B10.D2 donor and BALB/c recipient; syngeneic mice as controls). Ziritaxestat or nintedanib (60 mg/kg once daily [qd]) as active comparator was administered 21 d after BMT and continued for 35 d. Effects of ziritaxestat were assessed by clinical monitoring, histologic assessment of skin and lungs (dermal thickness, Ashcroft scores and collagen-covered area), immunofluorescence staining with Trichrome and Sirius Red for myofibroblasts, and biochemical analysis of collagen content, as measured by hydroxyproline levels.Results:Ziritaxestat 30 mg/kg bid for 35 days significantly reduced the clinical cutaneous score in the murine cGvHD model by 57% (p<0.05) compared with vehicle, and to a similar extent when compared with nintedanib 60 mg/kg (38%; p<0.05). Dermal accumulation of collagen and dermal thickness (Figure) were reduced with ziritaxestat 10 and 30 mg/kg compared with vehicle. At 30 mg/kg, ziritaxestat reversed the increase in the allogeneic model (p<0.001), returning dermal thickness to the levels in non-fibrotic control mice. Ziritaxestat also significantly reduced pulmonary fibrosis in the cGvHD model, with reductions in the fibrotic lung area (ziritaxestat 10 and 30 mg/kg; p<0.001 for both) and Ashcroft scores (ziritaxestat 30 mg/kg; p<0.05). Ziritaxestat was generally well tolerated.Conclusion:Ziritaxestat improved the histological, biochemical and clinical symptom readouts of dermal and pulmonary fibrosis in a murine model, consistent with a broad and rapid disease-modifying effect in SSc.Acknowledgements:This study was funded by Galapagos NV (Mechelen, Belgium). Medical writing/editorial support was provided by Ian Faulkner, PhD (Aspire Scientific, Bollington, UK) funded by Galapagos NV.Disclosure of Interests:Yun Zhang Employee of: 4D Science, Lena Summa Employee of: 4D Science, Bertrand Heckmann Shareholder of: Galapagos, Employee of: Galapagos, Jörg H.W. Distler Shareholder of: 4D Science, Consultant of: Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GlaxoSmithKline, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Grant/research support from: Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, Bristol Myers Squibb, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GlaxoSmithKline, Inventiva, Novartis, Sanofi-Aventis, RedX and UCB

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