Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Cell ; 168(6): 1041-1052.e18, 2017 03 09.
Article in English | MEDLINE | ID: mdl-28283060

ABSTRACT

Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems.


Subject(s)
Anaphylaxis/metabolism , Hematopoietic Stem Cells/immunology , Mast Cells/metabolism , Proto-Oncogene Proteins c-kit/metabolism , Signal Transduction , Stem Cell Factor/metabolism , Anaphylaxis/immunology , Animals , Dimerization , Humans , Mast Cells/immunology , Mice , Mice, Inbred C57BL , Models, Molecular , Protein Engineering , Proto-Oncogene Proteins c-kit/agonists , Proto-Oncogene Proteins c-kit/chemistry , Stem Cell Factor/chemistry , Stem Cell Factor/genetics
2.
Sci Transl Med ; 8(351): 351ra105, 2016 08 10.
Article in English | MEDLINE | ID: mdl-27510901

ABSTRACT

Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti-c-Kit conditioning to fully immunocompetent mice. The combined treatment leads to elimination of >99% of host HSCs and robust multilineage blood reconstitution after HSC transplantation. This targeted conditioning regimen that uses only biologic agents has the potential to transform the practice of HSC transplantation and enable its use in a wider spectrum of patients.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunotherapy/methods , Animals , CD47 Antigen/antagonists & inhibitors , CD47 Antigen/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Erythrocytes/metabolism , Flow Cytometry , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/physiology , Humans , Mice , Mice, Mutant Strains , Receptors, Fc/genetics , Receptors, Fc/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...