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BioOncology Watch Timely Information for Practicing
Physicians |
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JUNE 2000 Graft-versus-Host Disease (GVHD) Granulocyte-colony stimulating factor (G-CSF) mobilization of
dendritic cells (DCs). Mario Arpinati
and associates analyzed blood, leukapheresis, and bone marrow samples from
normal and G-CSF treated human donors to study the effects of G-CSF on the DC
population. G-CSF treatments (n=13)
increased peripheral blood DC2 counts (lymphoid DC which drive T-cell
differentiation to B-cell stimulating T helper 2 [Th2] cells) and did not
alter DC1 counts (myeloid DC which drive T-cell differentiation to cytotoxic
T lymphocyte generating T helper 1 [Th1] cells) compared to normal samples
(n=9). In addition, G-CSF mobilized
PBSC transplants (n=7) were found to contain higher doses of DC2 than marrow
transplants (n=15) (p=.006), whereas the dose of DC1 was comparable. These results may explain why overwhelming
acute GVHD does not develop after PBSC transplantation. Furthermore, altering the DC2 to DC1 ratio
by G-CSF mobilization provides a potential strategy to enhance the survival
of organ grafts. (Arpinati M, et al. Blood 2000;95:2484-2490) Monoclonal antibody (mAb) treatment.
Blockade of the CD40-CD154 pathway using anti-CD154
monoclonal antibody (mAb) has been shown to inhibit the graft-versus-host
disease (GVHD) activity of alloreactive CD8+ T cells. Edward Seung and
colleagues used a conditioning regimen of sublethal radiation with or without
anti-CD154 mAb therapy (to block the CD40-CD154 interaction) in BALB/c mice
transplanted with allogeneic C57BL/6 mouse bone marrow. In contrast to mice treated with radiation
only, mice given anti-CD154 mAb (n=9) did not develop GVHD and accepted
donor-origin, but not third party, skin allografts. This marrow transplantation protocol also allowed all chimeric
NOD/Lt mice with autoimmune diabetes (n=19) to accept pancreatic islet
allografts. Nobuhiro Tsukada et al
also used a murine model of acute GVHD to study the potential effectiveness
of blocking the CD134-CD134L (member of TNF family) interaction by the
administration of an anti-CD134L mAb.
Anti-CD134L mAb therapy (n=30) increased survival and reduced the
signs of acute GVHD compared to those mice receiving radiation and control
IgG (n=30). An assay of T-cell
proliferation showed a marked hyporesponsiveness to host alloantigen in
samples from mice treated with anti-CD134L mAb. Although these therapies have yet to be evaluated in tumor
models, these results suggest that mAb therapy may ameliorate GVHD and
facilitate transplantation tolerance induction. (Seung E, et al. Blood 2000;95:2175-2182 and Tsukada N,
et al. Blood
2000;95:2434-2439) Leukemia
Cytotoxic T lymphocytes (CTL) specific for the Wilm’s tumor gene
encoded transcription factor (WT1). Elevated
levels of WT1 expression have been observed in CD34+ progenitor cells
obtained from patients with acute and chronic myelogenous leukemias. Liquan Gao et al. investigated WT1 as a
target for CTLs. They generated
peptide-specific CTLs from MHC-mismatched donors and a 9 amino acid peptide
segment of WT1 (P126 peptide) was selected as the CTL target because it binds
to HLA-A0201 class I molecules. The
generated CTLs killed leukemia CD34+ cells obtained from leukemic cell lines
and from patients with chronic myelogenous leukemia. The CTLs were specific for leukemic
progenitor cells and HLA-A0202-negative cells, CD34- cells, and normal CD34+
cells were not effected. These
results show that the WT1 antigen is capable of directing CTL responses
selectively against leukemic progenitor cells. (Gao L, et al. Blood
2000;95:2198-2203) Tumor Cell Vaccination
Enhancement of graft-versus-tumor (GVT) activity. Larry Anderson and colleagues conducted
animal experiments to investigate whether post-transplant immunization of
allogeneic bone marrow transplantation (BMT) recipients could increase GVT
activity. Donor (C3H.SW mice) BM and
splenocytes were transplanted into MHC matched but minor histocompatibility
antigen mismatched recipients (C57BL/6 mice) and one month later the
recipients were immunized against either myelomonocytic leukemia cells (the
C1498 cell line) or fibrosarcoma cells (the 205 cell line) by subcutaneously
administered tumor cell vaccinations.
Micrometastases were established by tumor cell intravenous injection
10-14 days after vaccination. In both
tumor models, recipients treated with multiple vaccinations had longer
survival (p<.0001) and evidence of protection against tumor growth
compared to non-immune control animals. Immunity was tumor specific and no
exacerbation of graft-versus-host disease (GVHD) was observed. These experiments show that
post-transplant tumor immunization can induce GVT activity without increasing
GVHD. (Anderson LD, et al. Blood 2000;95:2426-2433) Cellular immune response mechanisms. Two recent studies further define the role
of Fas-mediated mechanisms in antitumor cellular immune responses. Antoni Ribas and coworkers demonstrated
that C3H mice, but not C57BL/6 mice, receiving multiple vaccinations with
dendritic cells transduced with the MART-1 gene unexpectedly had decreased
tumor protection compared to those mice receiving a single vaccination. This impaired immune response was
associated with an altered cytokine profile and was abrogated in studies
performed in Fas receptor-negative C3H mice.
Thus, the findings in the C3H mice may be attributed to a Fas-receptor
mediated clearance of antigen-specific type 1 cytokine-producing cells and
indicate that different individuals may respond differently to tumor
immunization according to HLA alleles, tumor antigens, and non-MHC
genes. In a second study, Masaki
Yasukawa et al. generated alloantigen-specific CD4+ and CD8+ lymphocytes with
Fas -/- or Fas +/- cell lines established from B-lymphocytes obtained from
members of a Fas-deficient family.
The cytotoxicity exerted by the CD4+ and CD8+ CTLs against Fas -/- and
Fas +/- cells was similar and was suppressed by an inhibitor of perforin-mediated
cytotoxicity (concanamycin A). These
data show that the cytotoxicity of human CD4+ and CD8+ CTLs is not mediated
by the Fas/Fas ligand system, but is accomplished via granule
exocytosis. (Ribas A, et al. Cancer Res 2000; 60:2218-2224 and
Yasukawa M, et al. Blood
2000;95:2352-2355) |
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