In vivo depletion of hematopoietic stem cells in the rat by an anti-CD45 (RT7) antibody.
Anti-CD45 monoclonal antibodies (mAbs) are potentially powerful tools for the depletion of mature leukocytes. As their application for immunotherapy also depends on their effects on bone marrow (BM) progeny, the in vivo effects of an anti-CD45 mAb (anti-RT7(a) mAb) on BM precursor cells were analyzed in a rat model. Anti-RT7(a) mAb treatment was performed in LEW.1W (RT1(u) RT7(a)) rats with the use of different dosages. In addition, major histocompatibility complex (MHC)-congenic BM transplantation making use of a diallelic polymorphism (RT7(a)/RT7(b)) of rat CD45 was applied. Following injection of anti-RT7(a) mAb into normal LEW.1W rats, T cells were profoundly depleted in blood, lymph nodes, and spleen, whereas B cells were coated only by the antibody. Single injection of anti-RT7(a) mAb in a high dose induced a lethal aplastic syndrome with severe thrombocytopenia. Rescue of antibody-treated animals with BM from congenic LEW.1W-7B rats (RT1(u) RT7(b)) and transplantation of BM from LEW.1W rats pretreated with anti-RT7(a) mAb into sublethally irradiated LEW.1W-7B recipients revealed a profound effect of the mAb on progeny of myeloid and T-cell lineage. Following repeated antibody treatment of stable mixed chimeras (RT7(b)/RT7(a)), very few RT7(a)-positive B cells were still detectable after 6 months and their number declined during the subsequent year. These observations show that this anti-RT7(a) mAb effectively depletes mature T cells as well as BM precursor cells of myeloid, T-cell, and thrombocytic lineage after in vivo application. In contrast, mature B cells are not depleted, but precursors also appear to be eliminated. Overall, the findings suggest that the anti-RT7(a) mAb efficiently depletes early rat hematopoietic stem cells.
Dahlke
Marc H
MH
Klinik für Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Germany.
Lauth
Oliver S
OS
Jäger
Mark D
MD
Roeseler
Till
T
Timrott
Kai
K
Jackobs
Stefan
S
Neipp
Michael
M
Wonigeit
Kurt
K
Schlitt
Hans J
HJ
D000818:Animals; D020296:Animals, Congenic; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D003165:Complement System Proteins / Q000235:genetics; D004306:Dose-Response Relationship, Immunologic; D005434:Flow Cytometry; D019337:Hematologic Neoplasms / Q000628:therapy; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D007700:Kinetics; D017493:Leukocyte Common Antigens / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D007958:Leukocyte Count; D008212:Lymphocyte Depletion / Q000379:methods; D051381:Rats; D011917:Rats, Inbred Lew; D013156:Splenectomy; D013921:Thrombocytopenia / Q000209:etiology; D018183:Transplantation Chimera
D000911:Antibodies, Monoclonal; D003165:Complement System Proteins; D017493:Leukocyte Common Antigens