Investigation of lymphocyte depletion and repopulation using alemtuzumab (Campath-1H) in cynomolgus monkeys.
As the target CD52 molecule is expressed on erythrocytes of most nonhuman primate strains, using alemtuzumab in these species would cause massive hemolysis. Six cynomolgus monkeys of Indonesian origin, screened by agglutination assay for absence of CD52 on erythrocytes, were administered alemtuzumab in a cumulative dose to a maximum of 60 mg/kg. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg alemtuzumab and was more profound than in monkeys treated with antithymocyte globulin (n = 5), as quantified by flow cytometry. Repopulation was suppressed by weekly injections of 10 mg/kg. Without MMF, repopulation of CD20(+)B cells and CD8(+)T cells was complete within 2 and 3 months, respectively, and repopulation of CD4(+)T cells was 67% after 1 year. MMF significantly delayed CD4(+)T-cell repopulation. Among repopulating CD4(+) and CD8(+) T cells, a phenotypic shift was observed from CD45RA(hi)CD62L(hi) naïve cells toward CD45RA(lo)CD62L(lo) effector memory cells. In lymph nodes, the depletion of naïve cells was more profound than of memory cells, which may have initiated a proliferation of memory cells. This model offers opportunities to investigate lymphocyte depletion/repopulation phenomena, as well as the efficacy of alemtuzumab in preclinical transplantation models.
Van Der Windt
D J
DJ
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.|Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Pittsburgh, PA.|Department of Surgery, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Smetanka
C
C
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
Macedo
C
C
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
He
J
J
Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Pittsburgh, PA.
Lakomy
R
R
Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Pittsburgh, PA.
Bottino
R
R
Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Pittsburgh, PA.
Ekser
B
B
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
Echeverri
G J
GJ
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.|Transplantation Unit, Fundacion Valle del Lili, Cali, Colombia.
Metes
D
D
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh, Pittsburgh, PA.
Ijzermans
J N M
JNM
Department of Surgery, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Trucco
M
M
Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, Pittsburgh, PA.
Cooper
D K C
DKC
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
Lakkis
F G
FG
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, PA.|Department of Immunology, University of Pittsburgh, Pittsburgh, PA.
D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology; D002455:Cell Division / Q000187:drug effects*; D005434:Flow Cytometry; D016130:Immunophenotyping; D008212:Lymphocyte Depletion; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology; D008252:Macaca fascicularis
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000074323:Alemtuzumab