Investigation of immunological approaches to enhance engraftment in a 1 Gy TBI canine hematopoietic stem cell transplantation model

Lange, Sandra; Altmann, Simone; Brandt, Bettina; Adam, Carsten; Riebau, Franziska; Vogel, Heike; Weirich, Volker; Hilgendorf, Inken; Storb, Rainer; Freund, Mathias; Junghanß, Christian

doi:10.1016/j.exphem.2008.09.011

Cited by 9 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All 8 dogs in this study initially engrafted, but toxic effects were significant. The initial engraftment levels in our study were comparable to former studies with 2 Gy TBI [2,12,21]. However, only 1 dog demonstrated a long-term engraftment.…”

Section: Discussionsupporting

confidence: 88%

Everolimus in Combination with Mycophenolate Mofetil as Pre- and Post-Transplantation Immunosuppression after Nonmyeloablative Hematopoietic Stem Cell Transplantation in Canine Littermates

Machka

Lange

Werner

et al. 2014

Biology of Blood and Marrow Transplantation

Self Cite

View full text Add to dashboard Cite

The mammalian target of rapamycin inhibitor everolimus (RAD001) is a successfully used immunosuppressant in solid-organ transplantation. Several studies have already used RAD001 in combination with calcineurin inhibitors after hematopoietic stem cell transplantation (HSCT). We investigated calcineurin inhibitor-free pre- and post-transplantation immunosuppression of RAD001 combined with mycophenolate mofetil (MMF) in a nonmyeloablative HSCT setting. After nonmyeloablative conditioning with 2 Gy total body irradiation, 8 dogs received HSCT from dog leukocyte antigen-identical siblings. Immunosuppressives were given at doses of 1.5 mg RAD001 twice daily from day -1 to +49, then tapered until day +56, and 20 mg/kg MMF from day 0 to +28, then tapered until day +42. An historical cyclosporin A (CsA)/MMF regimen was used in the control group. All dogs engrafted. Median platelet nadir amounted in all dogs to 0 × 10(9)/L (median, day +10; duration <50 × 10(9)/L, 22 days) and median leukocyte nadir was 1.0 × 10(9)/L (range, .1 to 2.5 × 10(9)/L; median, day +13). Eventually, 5 of 8 (63%) animals rejected their grafts. Two dogs died of infections on day +19 and +25. Pharmacokinetics of RAD001 and MMF showed median trough levels of 19.1 (range, 10.5 to 43.2) μg/L and .3 (.1 to 1.3) mg/L, respectively. The median area under the curve was 325 (range, 178 to 593) μg/L × hour for RAD001 and 29.6 (range, 7.9 to 40.5) ng/L × hour for MMF. All dogs developed clinically mucosal viral infections during the clinical course. Compared with the control group, the level of toxicities for RAD001/MMF increased in all qualities. Combined immunosuppression of RAD001 and MMF after nonmyeloablative HSCT is associated with significant toxicities, including a prolonged platelet recovery time as well as increased infections compared to the CsA/MMF regimen.

show abstract

Section: Discussionsupporting

confidence: 88%

Everolimus in Combination with Mycophenolate Mofetil as Pre- and Post-Transplantation Immunosuppression after Nonmyeloablative Hematopoietic Stem Cell Transplantation in Canine Littermates

Machka

Lange

Werner

et al. 2014

Biology of Blood and Marrow Transplantation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hematologic recovery in dogs after application of a starting dose of 0.25 mg and 15 mg/kg CsA twice a day after HSCT (n 5 10). Median leukocyte and platelet counts after RAD001 treatment (solid line) were compared with the MMF-related toxicity (dotted line, historic data[31]).…”

mentioning

confidence: 99%

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Junghanß

Rathsack

Wacke

et al. 2012

Biology of Blood and Marrow Transplantation

Self Cite

View full text Add to dashboard Cite

Everolimus (RAD001) is an mTOR inhibitor that has been successfully used as an immunosuppressant in solid-organ transplantation. Data in allogeneic hematopoietic stem cell transplantation (HSCT) is limited. This study aimed to investigate pharmacokinetics, safety, and efficacy of RAD001 in a canine allogeneic HSCT model. First, pharmacokinetics of RAD001 were performed in healthy dogs in order to determine the appropriate dosing. Doses of 0.25 mg RAD001 twice daily in combination with 15 mg/kg cyclosporin A (CsA) twice daily were identified as appropriate starting doses to achieve the targeted range of RAD001 (3-8 μg/L) when orally administered. Subsequently, 10 dogs were transplanted using 2 Gy total body irradiation (TBI) for conditioning and 0.25 mg RAD001 twice daily plus 15 mg/kg CsA twice daily for pre- and posttransplantation immunosuppression. Seven of the 10 transplanted dogs were maintained at the starting RAD001 dose throughout the study. For the remaining 3 dogs, dose adjustments were necessary. RAD001 accumulation over time did not occur. All dogs initially engrafted. Five dogs eventually rejected the graft (weeks 10, 10, 13, 27, and 56). Two dogs died of pneumonia (weeks 8 and 72) but were chimeric until then. Total cholesterol rose from median 4.1 mmol/L (3.5-5.7 mmol/L) before HSCT to 6.0 mmol/l (5.0-8.5 mmol/l) at day 21 after HSCT, but remained always within normal range. Changes in creatinine and triglyceride values were not observed. Long-term engraftment rates were inferior to sirolimus/CsA and mycophenolate mofetil (MMF)/CsA regimen, respectively. RAD001/CsA caused a more pronounced reduction of platelet counts to median 2 × 10(9)/L (range: 0-21 × 10(9)/L) and longer time to platelet recovery of 21 days (range: 14-24 days) compared with MMF/CsA. CsA c(2h) levels were significantly enhanced in the RAD001/CsA regimen, but c(0h) and area under the curve from 0 to 12 hours (AUC(0-12h)) values did not differ compared with an MMF/CsA immunosuppression. In summary, immunosuppression consisting of RAD001 and CsA is well tolerated but not as efficient as with other established immunosuppressants in a canine nonmyeloablative HSCT regimen. Hence, our study does not support the application of RAD001/CsA as standard practice in this setting.

show abstract

“…In the case of stem cell transplantation into blood circulation, such as hematopoietic stem cells [21] and bone marrow-derived stem cells [22], scaffolds are not necessary. However, in the case of direct injection of stem cells into damaged and/or degenerated local tissues with wide open areas in the absence of fascia, maintaining cell-to-cell relationships, such as autocrine and/or paracrine factors, is very important.…”

Section: Discussionmentioning

confidence: 99%

Micro 3D Culture System using Hyaluronan-Collagen Capsule for Skeletal Muscle-Derived Stem Cells~!2009-07-29~!2010-02-03~!2010-04-28~!

Tono-Okada¹,

Okada²,

Masuda³

et al. 2010

TOTERMJ

View full text Add to dashboard Cite

Abstract:In order to hold non-adhesive type cells while maintaining cellular interactions and various autocrine/paracrine factors, a micro 3D culture system using Hyaluronan (HA)-type I collagen capsules was investigated as a possible scaffold for cell transplantation. Skeletal muscle-derived enzymatically extracted cells, which include numerous non-adhesive type stem cells were cultured in conventional liquid DMEM with and without encapsulation in HA-collagen capsules, and cellular proliferation/differentiation were compared. Results indicate that encapsulation does not disturb any cellular proliferation/differentiation after 7 days of culture. Gradual increases in vascular endothelial growth factor are also confirmed in HA-collagen culture, which may be induced by slower diffusion of autocrine/paracrine factors in the capsule and may benefit cellular proliferation/differentiation. Cell-holding capacity of encapsulation was also tested by in vivo transplantation into wide-open muscle scars without fascia. Encapsulation significantly contributes to higher donor cell implantation ratio and damaged muscle mass recovery than that of non-capsulation.

show abstract

Investigation of immunological approaches to enhance engraftment in a 1 Gy TBI canine hematopoietic stem cell transplantation model

Cited by 9 publications

References 31 publications

Everolimus in Combination with Mycophenolate Mofetil as Pre- and Post-Transplantation Immunosuppression after Nonmyeloablative Hematopoietic Stem Cell Transplantation in Canine Littermates

Everolimus in Combination with Mycophenolate Mofetil as Pre- and Post-Transplantation Immunosuppression after Nonmyeloablative Hematopoietic Stem Cell Transplantation in Canine Littermates

Everolimus in Combination with Cyclosporin A as Pre- and Posttransplantation Immunosuppressive Therapy in Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Micro 3D Culture System using Hyaluronan-Collagen Capsule for Skeletal Muscle-Derived Stem Cells~!2009-07-29~!2010-02-03~!2010-04-28~!

Contact Info

Product

Resources

About