CMRF-44 antibody-mediated depletion of activated human dendridic cells: a potential means for improving allograft survival.
BACKGROUND
Activated dendritic cells (DC) initiate immune responses by presenting antigen, including alloantigen from tissue grafts, to T lymphocytes. The potential to deplete or inactivate differentiated-activated DC during allogeneic transplantation represents a new approach to immunosuppression.


METHODS
The authors investigated the potential of the monoclonal antibody CMRF-44, which has specificity for a DC-associated differentiation-activation antigen, to induce complement-mediated lysis of activated human DC. Peripheral blood mononuclear cells (PBMC), or purified DC preparations, were cultured overnight to activate endogenous DC, resulting in the expression of CMRF-44 antigen and CD83. These were then treated with CMRF-44 and complement. Depletion of activated DC was monitored by flow cytometry.


RESULTS
Eighty-nine percent of activated (CD83+) DC in cultured PBMC were depleted by treatment with CMRF-44 and autologous serum (AS) (complement source; mean percentage of CD83+-CD14--CD19- cells=0.06%; cf 0.50% for heat-inactivated AS controls, P<0.0005, n=7). Ninety-five percent of cultured purified myeloid DC were depleted by this treatment, compared with only 43% of similarly treated lymphoid DC. Overnight culture also increases CMRF-44 antigen on a proportion of B cells and mononuclears, but only 24% of these cells were depleted. This treatment considerably reduced the ability of PBMC to stimulate allogeneic CD4+ CD45RA+ T lymphocytes. Similarly, the T-cell proliferative responses to recall and naive antigens were significantly reduced.


CONCLUSIONS
CMRF-44 may be a suitable candidate for a new selective immunosuppressive strategy, targeting differentiated-activated but not resting DC. It may have applications in preventing GVHD in allogeneic bone marrow transplantation and facilitate immunoacceptance of solid organ allografts.
Koppi
Thelma
T
Department of Microbiology, University of Western Australia, QEII Medical Centre, Nedlands, Western Australia.
Munster
David J
DJ
Brown
Len
L
MacDonald
Kelli P A
KP
Hart
Derek N J
DN
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology*; D000941:Antigens / Q000494:pharmacology; D001790:Blood Physiological Phenomena; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology; D002452:Cell Count; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects; D006433:Hemocyanins / Q000494:pharmacology; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D009000:Monocytes / Q000502:physiology; D009994:Osmolar Concentration; D013745:Tetanus Toxoid / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000941:Antigens; C474761:CMRF-44 monoclonal antibody; D013745:Tetanus Toxoid; D003165:Complement System Proteins; D006433:Hemocyanins; D017493:Leukocyte Common Antigens; C032808:keyhole-limpet hemocyanin