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Prepublished online as a Blood First Edition Paper on April 30, 2002; DOI 10.1182/blood-2002-01-0068.
IMMUNOBIOLOGY
From the Departments of Hematology Oncology and
Experimental Therapeutics, Tufts New England Medical Center, Boston,
MA.
Extracorporeal photochemotherapy (ECP) has been shown to be an
effective therapy for patients with acute and chronic graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation, but
its biologic mechanism is not understood. We reported that clinical
response to ECP was associated not only with normalization of skewed
CD4/CD8 ratios but also with an increase in
CD3 Acute and chronic graft-versus-host disease (aGVHD
and cGVHD) represent a major cause of morbidity and mortality following allogeneic bone marrow transplantation (BMT).1 The
incidence of aGVHD ranges from 20% to 50% and is dependent on factors
related to the graft and to the effects of conditioning regimens on
host tissue. cGVHD affects 30% to 50% of successfully engrafted
patients and is thought to be related to ongoing alloreactivity against minor HLA-antigen mismatch between donor and
recipient.2
Extracorporeal photochemotherapy (photopheresis, ECP) involves
ex vivo exposure of leukapheresed peripheral blood mononuclear cells to
ultraviolet A (UVA) light in the presence of a DNA-intercalating agent,
8-methoxypsoralen (8-MOP), with subsequent reinfusion of the treated
cells. The total number of lymphocytes treated ex vivo per cycle has
been estimated to be between 5% and 15% of the total circulating
lymphocytes, and the total energy delivered by UVA light is estimated
to be 2 J/cm2 per lymphocyte.3 ECP has
demonstrated efficacy in the treatment of cutaneous T-cell
lymphoma4 (CTCL) and recently in the management of
T-cell-mediated diseases such as scleroderma and alloreactivity in
patients with solid organ and bone marrow allografts.5
Immunomodulatory effects of ECP have been explored most extensively in
the context of cutaneous T-cell lymphoma, in which the induction of
tumor-specific CD8+ effector cells has been demonstrated.
Induction of apoptosis in circulating tumor cells exposed to UVA and
8-MOP is believed to prime antigen-presenting dendritic cells (DCs)
with processed tumor antigens capable of inducing an antitumor immune
response. In patients with autoimmune diseases and GVHD, ECP appears to induce tolerance to alloreactive or autoreactive antigen-generated T-cell responses, but the immunomodulatory effects of ECP in autoimmune disorders are unclear. In scleroderma, identification of autoreactive T-cell clones supports a mechanism similar to that in CTCL.
Clinical responses to ECP were demonstrated in patients with cGVHD
initially by Rosetti et al,1 who demonstrated a selective effect of ECP on cytotoxic effector CD8+ T cells with no
change in CD4+ T-helper populations in 5 children with
cGVHD, suggesting a differential effect on T-cell subsets without a
clear explanation of how this effect was manifest. Recently, we
demonstrated not only an effect of ECP on T-cell subsets in cGVHD
patients but also a direct effect on circulating antigen-presenting DCs
and natural killer cell populations in patients with cGVHD who had
clinical response to ECP, and we hypothesized that the mechanism of
action of ECP in cGVHD, and perhaps in autoimmune diseases, may be
related to the effects of the treatment on antigen presentation rather
than on effector T-cell populations.6
Dendritic cells are highly potent antigen-presenting cells (APCs) of
bone marrow origin that have been shown to stimulate primary and
secondary T- and B-cell responses.7 DCs are strategically distributed in tissues, they are constitutively rich in major histocompatibility complex (MHC) class II molecules, and they can be
readily induced to express the costimulatory molecules necessary for
activation of naive or resting T cells. To elicit an immune response,
DCs must undergo a maturation process initiated by inflammatory signals
and completed after contact with T cells. Maturation enables DCs to
migrate from peripheral tissues to lymphoid organs and to acquire a
potent antigen-presenting capacity. In addition, mature DCs are the
most relevant and initial source of cytokines that govern the
development of Th1 response.8
Two distinct types of DC precursors have been identified: myeloid
monocytes (pre-DC1) and plasmacytoid DC precursors (pre-DC2). In mouse
spleen, CD8+ "lymphoid" and CD8 To further elucidate the functional effects of ECP on alloantigen
presentation and cytokine production by effector T cells in cGVHD, we
examined DC function and helper T cell (Th1/Th2) differentiation. We
demonstrate that before ECP, DC from patients with cGVHD were capable
of inducing brisk autologous and allogeneic lymphocyte proliferation in
7 of 10 patients, whereas after in vivo exposure to ECP, autologous and
allogeneic T-cell proliferation was significantly attenuated. Further,
there was a significant decrease in DC1 (CD80+,
CD123+) compared with DC2 (CD83+,
CD86+) dendritic cells, with a resultant shift from a
predominantly Th1 (interferon- Reagents
Patients
Generation of dendritic cells from monocytes Fresh peripheral blood mononuclear cells (PBMCs) from patients were isolated by Ficoll-Hypaque (Amersham-Pharmacia Biotech, Uppsala, Sweden) gradient centrifugation. Nonadherent cells were removed by incubation of cells in culture flasks for 16 hours in RPMI 1640 complete medium (10% human AB serum, 50 µg/mL glutathione, 50 µg/mL streptomycin, and 50 µg/mL penicillin) at 5% CO2 and 37°C. Nonadherent cells were frozen at 80°C.
To induce DC differentiation, monocytes were cultured in 24-well plates
(Costar, Cambridge, MA) at 5 × 105 cells/well in AIM V
supplemented with 3% heat-inactivated human AB serum, 1000 IU/mL IL-4,
and 1000 IU/mL GM-CSF at 37°C in 5% CO2 for 4 days. DCs
were pulsed once with tetanus toxoid concentration at 0.01 fL/mL on day 3. Antigen was removed by washing the cells and
renewing the supplemented medium. The maturation-inducing agent TNF- Flow cytometry Cell staining was performed on 1 × 105 cells/mL with the following phycoerythrin (PE) or fluorescein isothiocyanate (FITC)-conjugated monoclonal antibodies: CD3 FITC, CD4 FITC, CD8 PE, CD25 PE, CD28 PE, CD56 PE, CD69 FITC, CD80 PE (B7-1), CD83 PE, CD86 PE (B7-2), and CD123 PE (Becton Dickinson, San Jose, CA). Cells were stained for 30 minutes in PBS with 0.05% fetal bovine serum (FBS), 2 mM EDTA, and 0.01% sodium azide. Cells were washed twice for 5 minutes in PBS with 0.05% FBS, 2 mM EDTA, and 0.01% sodium azide and were fixed with 1% paraformaldehyde in PBS. Ten thousand cells were analyzed by means of a FACScan (Becton Dickinson) equipped with a 488-nm argon laser. All isotype controls were set to be less than 2% positive for statistical analysis.Mixed-lymphocyte reaction Autologous lymphocytes from GVHD patients treated with ECP or allogeneic lymphocytes from healthy donors were cultured at 103 cells/well in 96-well plates (Costar) in AIM V supplemented with 3% heat-inactivated human AB serum with increasing numbers of irradiated DCs (30 Gy from a cesium Cs 137 source). Cells were pulsed with tetanus toxoid. Thymidine incorporation was measured in triplicate on day 6 by an 18-hour pulse with [3H]-thymidine (1 µCi/well [0.037 MBq/well]) (NEN, Boston, MA). Cells were harvested, and [3H]-thymidine incorporation was measured by -liquid
scintillation counter.
Antigen presentation Isolated pre- and post-ECP autologous lymphocytes were cultured at 103 cells/well in 96-well plates in AIM V and 3% heat-inactivated human AB serum. Autologous DCs were irradiated and added 1 × 104, 5 × 103, 2.5 × 103, and 1.25 × 103 cells per well to obtain T/DC ratios of 10:1, 20:1, 40:1, and 60:1, respectively. Proliferation of antigen-specific lymphocytes was evaluated in triplicate after 6-day exposure to tetanus toxoid by measuring [3H]-thymidine uptake during the last 18 hours.Separation of Th-cell subpopulations PBMCs were pulsed to staphylococcal enterotoxin-B protein (10 µg/mL) for 16 hours in complete medium. Cells (1 × 106) were washed with PBS supplemented with 0.5% bovine serum albumin (BSA) and 2 mM EDTA. Cells were incubated with cytokine-catch reagent (IFN- , IL-4, or IL-10) in
complete medium for 45 minutes at 37°C. Cells were labeled with PE-
or FITC-conjugated cytokine detection antibodies CD8 PE-IFN-
FITC, CD4 FITC-IL-4 PE, and CD4 FITC-IL-10 PE (Miltenyi Biotech,
Auburn, CA)11 for 10 minutes. Cells were washed twice
with PBS supplemented with 0.5% BSA and 2 mM EDTA. Cytokine-secreted
T-cell subsets were detected by flow cytometry using a 388-nm
argon laser. Data were analyzed using the Student t test and
were shown as the mean ± SE. P  .05 was considered significant.
Ten consecutive patients undergoing ECP for cGVHD after
allogeneic bone marrow transplantation were studied. As we previously reported, 9 of 10 responded to treatment with improvement in
sclerodermatous skin changes and in oral, musculoskeletal, hepatic, and
lung involvement. Patients received ECP for 2 consecutive days every 2 weeks. Lymphocyte and dendritic cell subsets and functional analysis
were performed before initiation and at the completion of day 2 (after
photopheresis) of each photopheresis cycle. Patients were
treated for a minimum of 6 months and until the response plateau.
Peripheral blood DCs were differentiated from monocytes and stem cells
in the presence of GM-CSF, IL-4, and TNF-
DC functional activity before and after ECP was measured by antigen
presentation to autologous and allogeneic lymphocytes in MLR assays.
DCs generated from PBMCs both before and after ECP at 3 different times
over the course of 1 year of treatment were irradiated and incubated
with autologous and allogeneic lymphocytes in variable T/DC numbers in
the presence of tetanus toxoid for 6 days. Cell proliferation was
measured by [3H]-thymidine uptake. Before ECP treatment,
brisk proliferation of autologous and allogeneic T cells was noted.
Interestingly, the proliferation of autologous T cells was greater than
that of allogeneic T cells in 7 of 10 patients (Table
2). Of the 3 patients in whom there was
greater stimulation with allogeneic T cells, 2 responded to ECP and one
had no response but had received a donor lymphocyte infusion (DLI) for
recurrent lymphoma. At the completion of the first ECP treatment,
allogeneic and autologous lymphocyte proliferation were significantly
blunted in all 10 patients, as shown in Figure
2, demonstrating an effect of ECP on
antigen presentation by DCs.
Because the observed effects of ECP on DC subpopulations would be
anticipated to result in functional skewing of cytokine secretion from
Th1 to Th2 cytokines, we evaluated Th1/Th2 ratios before and after ECP
using cytokine capture assays. After antigen stimulation of peripheral
blood lymphocytes with staphylococcal enterotoxin B, IFN-
The pathogenesis of cGVHD is controversial and may be related to
an extension of the acute alloreactivity seen in aGVHD or to a
manifestation of dysfunctional immune reconstitution with generation of
tissue autoreactive T-cell clones and dysregulation of
CD4+CD25+ immune modulating T cells. In murine
GVHD models, donor CD4-enriched cells of Th2 phenotype have
been shown to prevent GVHD without affecting engraftment, suggesting
that they play a role in down-regulating the TH1
response.12 Similarly, in chronic GVHD, the up-regulation of TH1 cytokines IFN- Dendritic cells are capable of presenting antigens to helper T cells, including naive T cells, and are likely important for inducing T-cell responses to foreign (allogeneic) MHC molecules in tissue allografts. The MLR is a useful in vitro model of direct T-cell recognition of allogeneic MHC gene products and is used as a predictive test of cell-mediated graft rejection. Alloreactive CD4+ and CD8+ T cells are stimulated during allogeneic MLR. CD8+ T cells differentiate into CTLs and are indistinguishable from self-class MHC I-restricted CTLs specific for foreign protein antigens. The CD4+ T cells differentiate into Th1 and Th2 cells. Donor and recipient APCs are likely to be involved in the process of graft rejection. The most important APCs stimulating an antigraft response are likely to be DCs, either of donor origin and resident in the interstitium of the graft or of recipient origin and entering the graft through the blood supply. These APCs may stimulate recipient T cells within the graft. It is also possible that donor APCs migrate from the graft into draining lymph nodes, where they activate naive alloreactive T cells by the direct pathway. We demonstrate here that ECP alters host (autologous) lymphocyte
proliferation in MLR by modulating DC antigen presentation and
differentiation of DC subtypes, favoring a decrease in DC1 and an
increase in DC2 cells (Figure 4). The
CD123+ lymphoid DC1 dendritic cells produce large amounts
of IFN-
Although the paradigm of GVHD is based on alloreactive donor T cells
recognizing foreign histocompatibility antigens of the host, there is
now substantial experimental and clinical evidence to implicate a
dysregulation of cytokine networks as a primary cause for the induction
and maintenance of GVHD. The balance between Th1 cytokines (IL-2,
IFN- To elucidate ECP effects on helper T-cell subsets in cGVHD, we
evaluated the helper T-cell subsets by their specific cytokine profile.
We observed that Th1 cells are decreased by ECP whereas Th2 cells are
increased over the 12-month treatment. Current models of alloreactivity
in acute GVHD implicate Th1 cells in the afferent arm and cytokine
production by monocytes and macrophages in the efferent
arm.20,21 In addition, Th2 cells have been used
experimentally to prevent GVHD in a murine model.22,23 Th1
cells induce the activation of macrophages, resulting in delayed-type
hypersensitivity responses and the killing of intracellular parasites.
In contrast, Th2 cells control humoral responses, including the
production of IgE-associated eosinophilia.23 An important
feature of Th1 and Th2 cells is the ability of one subset to regulate
the activity of the other. This occurs at the level of the effector
cells triggered by these subsets, as indicated by the inhibitory
effects of IFN- Antigen-specific T-cell responses are characterized by distinct
profiles of secreted cytokines. Rissoan et al27 have
demonstrated that polarization of the T-cell response into Th1 or Th2
depends on the type of APC. DC1 induces Th1 responses whereas DC2
induces Th2 responses.9 It has been proposed that DC2
might be responsible for maintaining peripheral T-cell tolerance to
self-antigens. Therefore, inducing the proliferation of
antigen-specific T cells might be obligatory for DC1 but not for
DC2.28 During inflammatory or immune responses initiated
by macrophages and DC1, however, the secretion of TNF- Direct presentation of donor alloantigens by resident host DC, however,
is likely to exert a dominant effect on the activation of donor T
cells, resulting in aGVHD and cGVHD.32 Donor DC
engraftment in recipients of allogeneic transplants has been associated
with prolonged organ transplant survival.33,34 Donor DC1
would activate allogeneic host T cells to produce IFN- The modulation of DC subpopulations correlated with clinical response. Of 9 patients who demonstrated a decrease in DC1 and an increase in DC2 cells, 8 had a response to ECP in at least one target organ. Of 2 patients with lung involvement, neither demonstrated a response in the lung. One had early relapse of lymphoma and underwent DLI, whereas the other had a response in skin GHVD but no change in pulmonary function. The patient who had no response in any target organ (patient 10) demonstrated a decrease in DC1 and DC2 populations and, therefore, demonstrated no selective effect of ECP. Interestingly, this patient demonstrated similar changes in T-cell cytokine profile with attenuation of Th1 activity. These results suggest that selective changes in DC subsets might predict for response to ECP, but these observations must be confirmed in larger numbers of patients. In summary, our data suggest that ECP has a direct effect to modulate APC function in patients with cGVHD. The net inhibitory effect of ECP on activated T cells and APCs favors attenuation of ongoing Th1-mediated events, thereby removing the inhibition to Th2 cytokine secretion and restoring balance between Th1 and Th2 cytokines. We have recently initiated a clinical trial to longitudinally examine the biomodulatory effects of ECP on lymphocyte and DC function in patients with cGVHD randomized to either ECP or to standard immunosuppressive therapy.
Submitted January 10, 2002; accepted March 25, 2002.
Prepublished online as Blood First Edition Paper, April 30, 2002; DOI 10.1182/blood-2002-01-0068.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Francine M. Foss, Departments of Hematology Oncology and Experimental Therapeutics, Tufts New England Medical Center, 750 Washington St, Boston, MA 02111; e-mail: ffoss{at}lifespan.org.
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Top
Abstract
Introduction
/CD56+ natural killer cells and a decrease
in the number of CD80+ and CD123+ circulating
dendritic cells (DCs). To further elucidate the effects of ECP on
activated lymphocyte subpopulations and the interaction between
effector lymphocytes and antigen-presenting DCs, we isolated and
characterized DC populations from patients with chronic GVHD undergoing
ECP therapy. Antigen-presenting activity of DCs was measured as
proliferation of antigen-stimulated autologous and allogeneic T cells
by mixed-lymphocyte reaction (MLR). In MLR assays the proliferation of
T cells was decreased in all 10 patients by a mean of 84% (range,
75%-95%; P 
(TNF-
present and future.
Vox Sang.
2000;78:197-201.