Anti-CD4 antibody–modulated transplants for GVHD prevention in hematopoietic cell transplantation
Abstract
Abstract Graft-versus-host disease (GVHD) remains one of the major complications following allogeneic hematopoietic cell transplantation. Currently, immunosuppressants are used for GVHD prophylaxis and treatment in most transplantation recipients. Due to their systemic, nonspecific mode of action, this treatment regimen is frequently associated with severe toxic side effects, opportunistic infections, as well as cancer relapse when treating hematologic malignancies. By using short-term ex vivo modulation of hematopoietic cell transplants with the anti-human CD4 antibody MAX.16H5, we have developed a novel immune tolerance–inducing strategy enabling potent GVHD prevention. Functional in vitro assays and transcriptome profiling data suggest impaired T-cell receptor signaling and a shift toward an interleukin-10–dependent regulatory phenotype as the primary mechanism of action of anti-human CD4 antibody treatment, leading to significantly reduced activation and proliferation of CD4+ and CD8+ T cells. A one-time incubation of hematopoietic transplants with MAX.16H5 prolongs survival of NSG (NOD.Cg-PrkdcSCID Il2rgtm1Wjl/SzJ) mice and reduces signs of GVHD manifestation as effectively as repeated application with clinically applied immunosuppressants, making it a safe and effective immunotherapy for GVHD prevention.
Article Details
Authors (16)
Kristina Roth
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Dennis Loeffler
2Department of Medical Bioinformatics, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Conny Blumert
2Department of Medical Bioinformatics, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Alexander Scholz
2Department of Medical Bioinformatics, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Kristin Reiche
Marcus Bauer
Claudia Wickenhauser
Denise Schiefer
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Nadja Hilger
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
André-René Blaudszun
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Jenifer Thees
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Jasmin Walter
U. Sandy Tretbar
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Ulrike Koehl
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Stephan Fricke
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
Ulrich Blache
1Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany