PMID- 12543110
OWN - NLM
STAT- MEDLINE
DCOM- 20030224
LR  - 20191025
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 31
IP  - 1
DP  - 2003 Jan
TI  - CD40 ligand-specific antibodies synergize with cyclophosphamide to promote 
      long-term transplantation tolerance across MHC barriers but inhibit 
      graft-vs-leukemia effects of transplanted cells.
PG  - 81-8
AB  - OBJECTIVES: We previously demonstrated that allogeneic bone marrow 
      transplantation (BMT) after low-dose total lymphoid irradiation (200 cGy) and 
      depletion of donor-reactive cells with cyclophosphamide (Cy) converted recipients 
      to graft-vs-host disease (GVHD)-free chimeras tolerant to donor skin grafts. BMT 
      also generated strong graft-vs-leukemia (GVL) response. However, clinical 
      application of the protocol was hampered by the requirement for a relatively high 
      dose of Cy (200 mg/kg). In this study we have tried to minimize the Cy dose by a 
      concomitant blockade of CD40-CD40L interaction. MATERIALS AND METHODS: Mildly 
      irradiated BALB/c mice were primed with C57BL/6 BM cells (BM(1)) and skin graft 
      on day 0, injected with Cy (200 mg/kg or less) on day 1, and transplanted with a 
      second C57BL/6 BM cell inoculum (BM(2)) on day 2. CD40L-specific antibody (MR1) 
      was given with BM(1), BM(2), and 2 days later. Treated animals were monitored for 
      survival, chimerism, and skin allograft rejection. The GVL potential of 
      transplanted cells was examined in mice inoculated with BCL1 leukemia cells 
      before irradiation. RESULTS: Blocking CD40-CD40L interaction with MR1 mAb allowed 
      the reduction of a tolerance-generating Cy dose by 50%. Unfortunately, adding MR1 
      to the protocol reduced the GVL potential of the transplanted cells. Neither 
      low-dose Cy nor antibodies alone could downregulate donor or recipient immune 
      response. CONCLUSIONS: CD40L-specific antibodies synergize with Cy to induce 
      bilateral transplantation tolerance. Therefore, their use may be beneficial for 
      safer allogeneic BMT for nonmalignant indications. However, due to MR1-associated 
      reduction of GVL effects, MR1 should be considered with caution as conditioning 
      for BMT for leukemia-bearing recipients.
FAU - Prigozhina, Tatyana B
AU  - Prigozhina TB
AD  - Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah 
      University Hospital, Jerusalem, Israel
FAU - Gurevitch, Olga
AU  - Gurevitch O
FAU - Elkin, Gregory
AU  - Elkin G
FAU - Morecki, Shoshana
AU  - Morecki S
FAU - Yakovlev, Elena
AU  - Yakovlev E
FAU - Slavin, Shimon
AU  - Slavin S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (CD40 Antigens)
RN  - 0 (Immunoconjugates)
RN  - 0 (Immunosuppressive Agents)
RN  - 147205-72-9 (CD40 Ligand)
RN  - 7D0YB67S97 (Abatacept)
RN  - 8N3DW7272P (Cyclophosphamide)
SB  - IM
MH  - Abatacept
MH  - Animals
MH  - Antibodies, Monoclonal/*pharmacology
MH  - *Bone Marrow Transplantation
MH  - CD40 Antigens/immunology
MH  - CD40 Ligand/*immunology
MH  - Cyclophosphamide/*pharmacology
MH  - Drug Synergism
MH  - Graft Enhancement, Immunologic
MH  - Graft vs Leukemia Effect/*drug effects
MH  - Immunoconjugates/pharmacology/therapeutic use
MH  - Immunosuppressive Agents/*pharmacology/therapeutic use
MH  - Lymphocyte Depletion/*methods
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Radiation Chimera
MH  - Safety
MH  - Skin Transplantation
MH  - Transplantation, Homologous/immunology
EDAT- 2003/01/25 04:00
MHDA- 2003/02/25 04:00
CRDT- 2003/01/25 04:00
PHST- 2003/01/25 04:00 [pubmed]
PHST- 2003/02/25 04:00 [medline]
PHST- 2003/01/25 04:00 [entrez]
AID - S0301472X02010093 [pii]
AID - 10.1016/s0301-472x(02)01009-3 [doi]
PST - ppublish
SO  - Exp Hematol. 2003 Jan;31(1):81-8. doi: 10.1016/s0301-472x(02)01009-3.