Publications by authors named "Lilly Stahl"

6 Publications

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Reduction of Graft-versus-Host-Disease in NOD.Cg-Prkdc Il2rg/SzJ (NSG) Mice by Cotransplantation of Syngeneic Human Umbilical Cord-Derived Mesenchymal Stromal Cells.

Transplant Cell Ther 2021 May 5. Epub 2021 May 5.

Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.

Graft-versus-host disease (GVHD) is one of the major complications following hematopoietic stem cell transplantation, which remains the sole curative therapy for many malignant diseases of the hematopoietic system. The immunomodulatory potential of mesenchymal stromal cells (MSCs) to treat GVHD is currently being tested in various preclinical and clinical trials. Because the results of the preclinical and clinical trials on the use of MSCs to treat GVHD have not been consistent, we analyzed the potential beneficial effects of syngeneic versus allogenic treatment, culture expansion of MSCs, and various MSC cell doses and time points of MSC transplantation in a murine GVHD model. We established the murine GVHD model based on the transplantation of umbilical cord blood-derived hematopoietic stem cells (UC-HSCs) and used this model to assess the therapeutic potential of umbilical cord blood-derived MSCs (UC-MSCs). The use of HSC and MSC populations derived from the same donor allowed us to exclude third-party cells and test the UC-HSCs and UC-MSCs in a matched setting. Moreover, we were able to compare various doses, transplantation time points, and the influence of culture expansion of MSCs on the impact of treatment. This resulted in 16 different treatment groups. The most efficient setting for treatment of UC-HSC-induced GVHD reactions was based on the simultaneous administration of 1 × 10 culture-expanded, syngeneically matched UC-MSCs. This therapy effectively reduced the number of CD8 T cells in the blood, protected the mice from weight loss, and prolonged their survival until the end of observation period. Taken together, our data show beneficial effects of (1) syngeneic over allogeneic UC-HSCs and UC-MSCs, (2) culture-expanded cells over freshly isolated primary cells, (3) simultaneous over sequential administration, and (4) high doses of UC-MSCs. The animal model of GVHD established here is now available for more detailed studies, including a comparative analysis of the efficacy of MSCs derived from alternative sources, such as adipose tissue and bone marrow.
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http://dx.doi.org/10.1016/j.jtct.2021.04.018DOI Listing
May 2021

CAR-Expressing Natural Killer Cells for Cancer Retargeting.

Transfus Med Hemother 2019 Feb 5;46(1):4-13. Epub 2019 Feb 5.

Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.

Since the approval in 2017 and the outstanding success of Kymriah® and Yescarta®, the number of clinical trials investigating the safety and efficacy of chimeric antigen receptor-modified autologous T cells has been constantly rising. Currently, more than 200 clinical trials are listed on clinicaltrial.gov. In contrast to CAR-T cells, natural killer (NK) cells can be used from allogeneic donors as an "off the shelf product" and provide alternative candidates for cancer retargeting. This review summarises preclinical results of CAR-engineered NK cells using both primary human NK cells and the cell line NK-92, and provides an overview about the first clinical CAR-NK cell studies targeting haematological malignancies and solid tumours, respectively.
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http://dx.doi.org/10.1159/000495771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558329PMC
February 2019

The Epitope-Specific Anti-human CD4 Antibody MAX.16H5 and Its Role in Immune Tolerance.

Front Immunol 2019 24;10:1035. Epub 2019 May 24.

Immune Tolerance Unit, Fraunhofer Institute of Cell Therapy and Immunology, Leipzig, Germany.

T cell modulation in the clinical background of autoimmune diseases or allogeneic cell and organ transplantations with concurrent preservation of their natural immunological functions (e.g., pathogen defense) is the major obstacle in immunology. An anti-human CD4 antibody (MAX.16H5) was applied intravenously in clinical trials for the treatment of autoimmune diseases (e.g., rheumatoid arthritis) and acute late-onset rejection after transplantation of a renal allograft. The response rates were remarkable and no critical allergic problems or side effects were obtained. During the treatment of autoimmune diseases with the murine MAX.16H5 IgG antibody its effector mechanisms with effects on lymphocytes, cytokines, laboratory and clinical parameters, adverse effects as well as pharmacodynamics and kinetics were studied in detail. However, as the possibility of developing immune reactions against the murine IgG Fc-part remains, the murine antibody was chimerized, inheriting CD4-directed variable domains of the MAX.16H5 IgG connected to a human IgG backbone. Both antibodies were studied and in specific humanized mouse transplantation models with a new scope. By incubation of an allogeneic immune cell transplant with MAX.16H5 a new therapy strategy has emerged for the first time enabling both the preservation of the graft-vs.-leukemia (GVL) effect and the permanent suppression of the acute graft-vs.-host disease (aGVHD) without conventional immunosuppression. In this review, we especially focus on experimental data and clinical trials obtained from the treatment of autoimmune diseases with the murine MAX.16H5 IgG antibody. Insights gained from these trials have paved the way to better understand the effects with the chimerized MAX.16H5 IgG as novel therapeutic approach in the context of GVHD prevention.
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http://dx.doi.org/10.3389/fimmu.2019.01035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543443PMC
August 2020

Incubation of Immune Cell Grafts With MAX.16H5 IgG1 Anti-Human CD4 Antibody Prolonged Survival After Hematopoietic Stem Cell Transplantation in a Mouse Model for Fms Like Tyrosine Kinase 3 Positive Acute Myeloid Leukemia.

Front Immunol 2018 22;9:2408. Epub 2018 Oct 22.

Immune Tolerance, Immunology, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.

Despite the constant development of innovative therapeutic options for hematological malignancies, the gold-standard therapy regimen for curative treatment often includes allogeneic hematopoietic stem cell transplantation (HSCT). The graft-vs.-leukemia effect (GVL) is one of the main therapeutic goals that arises from HSCT. On the other hand, graft-vs.-host disease (GVHD) is still one of the main and most serious complications following allogeneic HSCT. In acute myeloid leukemia (AML), HSCT together with high-dose chemotherapy is used as a treatment option. An aggressive progression of the disease, a decreased response to treatment, and a poor prognosis are connected to internal tandem duplication (ITD) mutations in the Fms like tyrosine kinase 3 (FLT3) gene, which affects around 30% of AML patients. In this study, C3H/HeN mice received an allogeneic graft together with 32D-FLT3 AML cells to induce acute GVHD and GVL. It was examined if pre-incubation of the graft with the anti-human cluster of differentiation (CD) 4 antibody MAX.16H5 IgG prevented the development of GVHD and whether the graft function was impaired. Animals receiving grafts pre-incubated with the antibody together with FLT3 AML cells survived significantly longer than mice receiving untreated grafts. The observed prolonged survival due to MAX.16H5 incubation of immune cell grafts prior to transplantation may allow an extended application of additional targeted strategies in the treatment of AML.
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http://dx.doi.org/10.3389/fimmu.2018.02408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204383PMC
October 2019

Effect of combined sublethal X-ray irradiation and cyclosporine A treatment in NOD scid gamma (NSG) mice.

Exp Anim 2019 Feb 3;68(1):1-11. Epub 2018 Aug 3.

Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, 04103 Leipzig, Germany.

Cyclosporine A (CsA) is used in hematopoietic stem cell transplantations (HSCT) to prevent graft-versus-host disease (GvHD). GvHD is the most severe side effect of allogeneic HSCT and efficient therapies are lacking. Mouse models are an essential tool for assessing potential new therapeutic strategies. Our aim is to mimic a clinical setting as close as possible using CsA treatment after sublethal irradiation in NSG mice and thereby evaluate the feasibility of this mouse model for GvHD studies. The effect of CsA (7.5 mg/kg body weight) on sublethally X-ray irradiated (2 Gy) and non-irradiated NSG mice was tested. CsA was administered orally every twelve hours for nine days. Animals irradiated and treated with CsA showed a shorter survival (n=3/10) than irradiated animals treated with NaCl (n=10/10). Furthermore, combined therapy resulted in severe weight loss (82 ± 6% of initial weight, n=7, day 8), with weight recovery after the CsA application was ceased. A high number of apoptotic events in the liver was observed in these mice (0.431 ± 0.371 apoptotic cells/cm, n=2, compared to 0.027 ± 0.034 apoptotic cells/cm, n=5, in the non-irradiated group). Other adverse effects, including a decrease in white blood cell counts were non-CsA-specific manifestations of irradiation. The combination of CsA treatment with irradiation has a hepatotoxic and lethal effect on NSG mice, whereas the treatment without irradiation is tolerated. Therefore, when using in vivo models of GvHD in NSG mice, a combined treatment with CsA and X-ray irradiation should be avoided or carefully evaluated.
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http://dx.doi.org/10.1538/expanim.18-0056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389519PMC
February 2019

Attenuation of graft-versus-host-disease in NOD scid IL-2Rγ(-/-) (NSG) mice by ex vivo modulation of human CD4(+) T cells.

Cytometry A 2016 09 25;89(9):803-15. Epub 2016 Aug 25.

Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany.

NOD.Cg-Prkdc(scid) IL-2rg(tm1Wjl) /SzJ (NSG) mice are a valuable tool for studying Graft-versus-Host-Disease (GvHD) induced by human immune cells. We used a model of acute GvHD by transfer of human peripheral blood mononuclear cells (PBMCs) into NSG mice. The severity of GvHD was reflected by weight loss and was associated with engraftment of human cells and the expansion of leukocytes, particularly granulocytes and monocytes. Pre-treatment of PBMCs with the anti-human CD4 antibody MAX.16H5 IgG1 or IgG4 attenuated GvHD. The transplantation of 2 × 10(7) PBMCs without anti-human CD4 pre-treatment induced a severe GvHD (0% survival). In animals receiving 2 × 10(7) PBMCs pre-incubated with MAX.16H5 IgG1 or IgG4, GvHD development was reduced and survival was increased. Immune reconstitution was measured by flow cytometry and confirmed for human leukocytes (CD45), CD3(+) /CD8(+) cytotoxic T cells and CD3(+) /CD4(+) T helper cells. Human B cells (CD19) and monocytes (CD14) could not be detected. Histopathological analysis (TUNEL assay) of the gut of recipient animals showed significantly less apoptotic crypt cells in animals receiving a MAX.16H5 IgG1 pre-incubated graft. These findings indicate that pre-incubation of an allogeneic graft with an anti-human CD4 antibody may decrease the frequency and severity of GvHD after hematopoietic stem cell transplantation (HSCT) and the need of conventional immunosuppressive drugs. Moreover, this approach most probably provides a safer HSCT that must be confirmed in appropriate clinical trials in the future. © 2016 International Society for Advancement of Cytometry.
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http://dx.doi.org/10.1002/cyto.a.22930DOI Listing
September 2016