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DC2 Effect on Survival Following Allogeneic Bone Marrow Transplantation

DC2 Effect on Survival Following Allogeneic Bone Marrow Transplantation

ABSTRACT: The graft-vs-tumor effect is an important part of the curative potential of allogeneic transplantation. We characterized the effect of transplanted donor mononuclear cells on relapse- and event-free survival after allogeneic bone marrow transplantation (BMT). We studied 113 consecutive patients with hematologic malignancies who received non-T-cell-depleted BMT from human leukocyte antigen (HLA)-matched siblings. Most patients (n = 103) received busulfan (Myleran)-based conditioning, and all patients received standard short-course methotrexate and tacrolimus (Prograf) as graft-vs-host disease prophylaxis. Sixty-four patients had low-risk diagnoses (acute lymphoblastic leukemia/acute myeloid leukemia [first complete remission], myelodysplastic syndrome [refractory anemia/refractory anemia with ring sideroblasts], and chronic myeloid leukemia [first chronic phase]); 49 patients had high-risk diagnoses (all others). Cox regression analyses evaluated risk strata, age, gender, and the numbers of nucleated cells, CD3-positive T cells, CD34-positive hematopoietic cells, and type 2 dendritic cells (DC2) as covariates for event-free survival, relapse, and nonrelapse mortality. Recipients of larger numbers of DC2 cells had significantly lower event-free survival, a lower incidence of chronic graft-vs-host disease, and an increased incidence of relapse. Recipients of larger numbers of CD34-positive cells had improved event-free survival; recipients of fewer CD34-positive cells had delayed hematopoietic engraftment and increased death from infections. In conclusion, content of donor DC2 cells was associated with decreased chronic graft-vs-host disease and graft-vs-leukemia effects consistent with Th2/Tc2 polarization of donor T cells following allogeneic bone marrow transplantation. [ONCOLOGY 16(Suppl 1):19-26, 2002]

The aggregate 5-year survival for all patients with
leukemia or lymphomas undergoing autologous transplantation, or allogeneic
transplantation from human leukocyte antigen (HLA)-matched siblings, remains
approximately 50%.[1-7] A number of factors, including patient disease status,
age, conditioning regimen, and (for allogeneic recipients) type of graft-vs-host
disease prophylaxis, influence the probability of survival after
transplantation.[1,8,9] The most significant factor in predicting relapse-free
survival is the patient’s diagnosis (eg, chronic myeloid leukemia vs acute
lymphoblastic leukemia) and disease status at the time of transplant (eg,
chronic phase chronic myeloid leukemia vs blast crisis). The factors amenable to
manipulation include the conditioning regimen, graft-vs-host disease
prophylaxis, supportive care during the peritransplant period, and the quality
and quantity of donor cells in the graft.

The Role of CD34-Positive Cells and T Cells

The optimal numbers for each cell type in the bone marrow or peripheral blood
progenitor cell allograft are not known. A variety of studies support the role
of larger numbers of CD34-positive cells in the graft in faster hematopoietic
reconstitution after autologous and allogeneic transplantation.[10-15]
Transplantation with fewer than 1 × 106 CD34-positive cells/kg from T-cell-depleted
allogeneic bone marrow and peripheral blood stem cell grafts was associated with
increased relapse and treatment-related mortality.[11,16] Recipients of T-cell-depleted
bone marrow allografts have a decreased risk of developing graft-vs-host
disease,[17,18] but experience delayed immune reconstitution and have an
increased risk of infections, graft failure, and relapse.[19-22]

There are numerous commercially available devices to positively select
CD34-positive hematopoietic progenitors and passively remove T cells. However,
the higher rates of relapse after T-cell-depleted allografts are unacceptable.
Indeed, a randomized, multicenter phase III study of CD34-positive cell
selection in allogeneic peripheral blood stem cell transplantation was recently
amended to exclude high-risk patients because of significantly higher relapse
rates among recipients of CD34-positive selected grafts.

Dendritic Cells

Dendritic cells have a specialized capacity to present peptide antigens to T
cells and regulate the initiation of the immune response.[23,24] There is
significant heterogeneity within the dendritic cell lineage. Dendritic cells
develop from hematopoietic progenitor "stem" cells under the influence
of cytokines that act during early myelomonocytic differentiation.[25-32]
Phenotypic and functional analyses have demonstrated two general types of
dendritic cells—type 1 (DC1) and type 2 (DC2)—that differ in surface marker
expression as well as their functional effect on cognate T cells.

Studies of cytokines used to mobilize peripheral blood hematopoietic
progenitors have indicated increased numbers of DC1 cells after administration
of Flt3 and granulocyte-macrophage colony-stimulating factor (GM-CSF [Leukine]),
while increased numbers of DC2 cells have been noted after treatment with
granulocyte colony-stimulating factor (G-CSF [Neupogen]).[33] DC1 cells promote
Th1 immune responses in responding CD4-positive T cells characterized by
enhanced interferon (INF)-gamma, tumor necrosis factor (TNF), and interleukin
(IL)-12 synthesis. DC2 cells promote Th2 responses in CD4-positive T cells
characterized by IL-4 and IL-10 synthesis, and inhibition of INF-gamma and TNF
production in cognate T cells.[32] The effects of GM-CSF and G-CSF on the
content of different dendritic cell subtypes in the blood, and the functional
differences between DC1 and DC2, offer potential therapeutic indications for
these cytokines.[33]

Dendritic Cells in Hematopoietic Progenitor Cell Transplantation

Dendritic cells play an important role in the antitumor effect of autologous
and allogeneic transplantation. Antigen-primed dendritic cells have been used
with promising results in adoptive vaccination against tumors.[34,35] Bone
marrow contains monocytes and CD86-positive, CD34-positive progenitor cells that
can differentiate into DC1 cells in the presence of TNF and GM-CSF,[36-38] as
well as CD123bright dendritic cell progenitors that differentiate into DC2 cells
in the presence of IL-3.[29] Most studies involving hematopoietic progenitor
cell transplantation to date have examined the role of DC1 cells as a method of
adoptive immunotherapy for cancer following autologous hematopoietic progenitor
cell transplantation.[34]

One recent report, using a murine transplant model, indicated that only host
CD11c-positive dendritic cells (DC1 cells) were necessary for the development of
acute graft-vs-host disease.[39] Donor dendritic cells did not appear to
efficiently present host antigens via cross-priming in a way that led to the
initiation of graft-vs-host disease.[39] In this study, the possible effect of
donor dendritic cells on inhibiting graft-vs-host disease was not examined. The
potential role of increased numbers of donor DC2 cells in regulating graft-vs-host
disease after G-CSF-mobilized allogeneic peripheral stem cell transplants has
recently been recognized.[33]

Adoptive Transfer of Immature Dendritic Cells

A recently published study in normal donors evaluated the ability of immature
dendritic cells to augment T-cell activation after in vitro exposure to
antigen.[40] Immature dendritic cells were derived from peripheral blood
monocytes and then exposed to the influenza peptide MP and keyhole limpet
hemocyanin. After return of these dendritic cells to the host, a marked decline
in the frequency of MP-specific INF-gamma-producing cells—which persisted
for 30 days—was noted. At the same time, the frequency of influenza-specific T
cells was unchanged, suggesting that the decrease in MP-specific INF-gamma-producing
cells was related to dendritic cell exposure to the antigen, rather than to a
global reduction in influenza response.

Also, this reduction in MP-specific INF-gamma-producing cells was
paralleled by an increase in the frequency of IL-10-producing MP-specific
cells, and a reduction in the ability of CD8-positive MP-specific cells to kill
target cells that had been loaded with MP peptides. There was no reduction in
the overall frequency of MP-specific T cells after return of the immature
dendritic cells to account for this change in antigen response.

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