| |
|
|
|
|
|
|
|||
|
TRANSPLANTATION
From the Department of Adult Oncology, Dana Farber
Cancer Institute, and the Division of Medical Oncology, Brigham and
Women's Hospital, Harvard Medical School, Boston, MA.
Blockade of B7/CD28 costimulation allows human haploidentical bone
marrow transplantation without graft-versus-host disease. This study
shows that blockade of B7/CD28 in anergizing mixed lymphocyte reaction
(MLR) cultures of peripheral blood mononuclear cells results in the
generation of alternatively activated macrophages (AAM The success of allogeneic bone marrow
transplantation (ABMT) is limited by the restricted donor pool and the
morbidity of graft-versus-host disease (GVHD). Donor T cells present in
the graft are mediators of GVHD. These donor T cells recognize host alloantigens and initiate a cascade of pathophysiologic events, which
result in the development of the clinical syndrome of
GVHD.1 Although GVHD can be prevented or ameliorated by
nonspecific immunosuppression or T-cell depletion, these
approaches are associated with increased infection and relapse rates
and, in the case of T-cell depletion, with increased graft failure
and lymphoproliferative disease.2
Studies in murine and subhuman primate models3-7 and more
recently a clinical trial in humans8 have provided great
promise that induction of T-cell anergy by blockade of costimulation
may prevent GVHD without nonspecific immunosuppression or T-cell
depletion. Anergy in vitro and its in vivo counterpart, tolerance, are
defined as the inability of viable, antigen-specific T cells to produce interleukin-2 (IL-2) or clonally expand when rechallenged with fully
competent antigen-presenting cells (APCs) delivering T-cell receptor
(TCR) and costimulatory signals.9 Anergy can be
induced when T cells are stimulated via TCR without costimulation or
IL-2.9,10 The B7-1/B7-2:CD28 pathway is the dominant
costimulatory pathway and has a critical role in the regulation of
T-cell viability, cytokine production, clonal expansion, and effector
function.11 The in vivo biologic significance and the
clinical relevance of this pathway have been validated in multiple
models for allogeneic renal, cardiac, and bone marrow
transplantation.3-5 We have shown that ex vivo blockade of
this pathway can inactivate the ability of donor haploidentical T cells
to recognize host alloantigens, thereby significantly reducing the
incidence of GVHD in patients undergoing haploidentical bone marrow
transplantation.8
T lymphocytes are the mediators of immunity, but their function is
under the control of APCs. Monocytes, the most abundant APCs, develop
from hematopoietic precursors, enter the bloodstream, and follow
divergent differentiation programs to form the wide variety of
morphologically and functionally distinct macrophages. The activation
and differentiation program of monocytes into macrophages is determined
by the presence of specific cytokines in selected microenvironments in
vivo or in culture supernatants in vitro. The balanced
macrophage-activation hypothesis states that in parallel with the
Th1/Th2 paradigm, macrophages can be divided into "classically" activated (CAM In our recent clinical study, histoincompatible bone marrow grafts
infused to patients after ex vivo blockade of the B7/CD28 pathway with
cytotoxic T lymphocyte antigen 4 (CTLA4)-Ig contained donor T
cells that exceeded by 1 or 2 orders of magnitude the suggested
threshold dose for minimizing GVHD.8 These patients had
additional high-risk factors for GVHD, including mismatching of the
donor and recipient, recurrent or persistent disease, irradiation-based conditioning, and cytomegalovirus positivity.8 Strikingly, the incidence of GVHD by this treatment approach not only was not
increased, but was significantly reduced as compared with that observed
after classic treatments. To determine whether besides inhibition of
CD28 signals, additional mechanisms may contribute to the
immunosuppression of host-specific donor T cells by this treatment
approach, we examined the immunophenotypic, molecular, and functional
properties of macrophages present in anergizing mixed lymphocyte
reaction (MLR) cultures of peripheral blood mononuclear cells (PBMCs).
Here we show that blockade of the B7/CD28 pathway results in the
generation of AAM Mixed lymphocyte reactions
Immunofluorescence and flow cytometry
Carboxyfluorescein diacetate succinimidyl ester labeling and analysis Carboxyfluorescein diacetate succinimidyl ester (CFSE) was purchased from Molecular Probes (Eugene, OR) and was reconstituted and used according to the manufacturer's protocol. Briefly, CFSE was diluted to a final concentration of 1 µM, and cells at a concentration of 107/mL were incubated at 37°C for 15 minutes in nonsupplemented RPMI (Gibco-BRL). The labeled cells were washed once with phosphate-buffered saline (PBS) containing 10% FCS, washed 3 times with PBS, and set to the indicated final concentration before initiation of MLR cultures.FITC-dextran uptake Uptake of FITC-dextran (molecular weight 70 000; Sigma, St Louis, MO) was evaluated as described previously.32 Briefly, CD14+ cells isolated from the indicated cultures were resuspended at 1 × 106 cells/mL in RPMI containing 10% FCS and 25 mM HEPES and incubated with FITC-dextran (1 mg/mL) for the indicated time intervals. The quantitative uptake of FITC-dextran was determined by flow cytometry.Cytokine enzyme-linked immunosorbent assay Culture supernatants were harvested at various time intervals of primary and secondary cultures and analyzed by enzyme-linked immunosorbent assay (ELISA) for cytokine levels of IL-2, IFN- , IL-4,
IL-10, and TGF- (R&D Systems). Assessment of total NO was done by
colorimetric enzymatic assay according to the manufacturer's protocol
(R&D Systems).
Reverse transcription-polymerase chain reaction Before RNA extraction, CD4+ and CD14+ cells isolated from MLR cultures by positive selection using anti-CD4 or -CD14 MicroBeads and MACS columns (Miltenyi Biotec), RNA was prepared by the RNAsol kit (Tel-Test, Friendswood, TX), and 2 µg RNA was used for reverse transcription as described previously.33 Polymerase chain reaction (PCR) amplification of cDNA was performed using specific oligonucleotides for IL-10, 5'-AAGCTGAGAACCAAGACCCAGACATCAAGGCG-3' (forward) and 5'-AGCTATCCCAGAG CCCAGATCCGATTTTGG-3' (reverse); glyceraldehyde-3-phosphate dehydrogenase (G3PDH), 5'-GTGAAGGTCGGAGTCAACG-3' (forward) and 5'-ACCAGGAAATGAGCTTGACAAA-3' (reverse); and AMAC-1, 5'-AAGCCCCAGCTCACTCTGAC-3' (forward) and 5'-ACCTGGCTTGGGGCACT-3' (reverse). Fifteen microliters of each of the final reaction products was analyzed by electrophoresis on 2% agarose gel containing ethidium bromide.Suppression subtractive hybridization Suppression subtractive hybridization34 was done with the use of the PCR-select cDNA subtraction kit (Clontech, Palo Alto, CA) according to the manufacturer's protocol. Briefly, cDNA from CD14+ cells isolated from anergizing cultures was used as "tester" (in which differential gene expression is searched), and cDNA from CD14+ cells isolated from priming cultures was used as "driver" (to which gene expression is compared). Tester cDNA was ligated to 2 different cDNA adaptors, tester and driver cDNAs were hybridized twice, and hybrid sequences were removed. Consequently, the remaining unhybridized cDNAs represented genes that are expressed in the tester but are absent from the driver mRNA. Subsequently, only unhybridized molecules containing adaptor sequences (and therefore originating from tester cDNA) were exponentially amplified by PCR using adaptor-specific primers. After a subtracted cDNA library was obtained, confirmation that individual clones were indeed differentially expressed was done by differential screening using the PCR-select differential screening kit (Clontech), as indicated by the manufacturer's protocol.
Blockade of B7/CD28 costimulation results in the generation of
macrophages with immunophenotypic markers of AAM To determine whether blockade of the B7/CD28 pathway with either
anti-B7 mAbs or CTLA4-Ig influenced the maturation and differentiation program of monocytes present in the anergizing cultures, we first examined surface markers that had been previously determined to be
differentially expressed in classically and alternatively activated macrophages.13,14 We examined the expression of CD14, MHC
class II, CD23, CD32, CD64, CD16, and CD163. At 48 hours of culture, there was a detectable difference in the expression of CD14 but not in
the expression of any of the other markers (Figure
1, top panel; and data not shown). At
days 5 and 7, a significantly enhanced expression of CD14 and MHC class
II was observed on monocytes isolated from cultures treated with
anti-B7 mAbs as compared with monocytes isolated from cultures with
medium alone (Figure 1, top and middle panels) or with control mAbs
(data not shown). Similar results were observed when CTLA4-Ig was used
instead of the combination of anti-B7-1 plus anti-B7-2 mAbs to induce
anergy (data not shown). Further analysis of markers expressed on
CD14+ cells in each population revealed that
CD14+ cells isolated from anergizing cultures treated with
either the combination of anti-B7-1 plus anti-B7-2 mAbs or with
CTLA4-Ig had increased expression of CD23 (Figure 1, lower panel; and
data not shown). The expression levels of CD64 and CD32 were only
slightly lower on CD14+ cells isolated from anergizing
cultures than on CD14+ cells isolated from cultures with
medium alone (data not shown). In contrast to previous
reports,18 no detectable differences were observed in the
expression of CD16 and CD163 on the CD14+ cells in the
different culture conditions (data not shown).
Because B7-1 (CD80) is induced and the very low constitutive levels of B7-2 (CD86) are up-regulated on monocytes after activation,36,37 we examined whether CD14+ cells isolated from the anergizing and priming cultures had different expression of B7-1 or B7-2. At all time intervals of culture tested, equivalent levels of B7-1 and B7-2 were induced on CD14+ cells in the anergizing and priming cultures (data not shown). Analysis of the dendritic cell-specific marker CD83 showed no detectable levels of CD83 expression in our cultures at any time point tested (data not shown). This is most likely due to the specific culture requirements for dendritic cell growth, which were not established in these classic MLR cultures. Distinct cytokine profile in anergizing cultures contributes to the
generation of AAM were detected in
CD14+ cells isolated from anergizing MLR cultures. Previous
studies have suggested that the differentiation program of macrophages is significantly influenced by cytokines present in distinct
microenvironments in vivo or in cultures in
vitro.13,14,32,38,39 Specifically, it has been shown that
classic activation of macrophages is induced by proinflammatory
cytokines such as IFN- , whereas alternative activation of
macrophages is induced by anti-inflammatory cytokines such as IL-4 and
IL-10.13,14 It is well documented that the B7/CD28
costimulatory pathway dramatically augments cytokine production by T
cells, and blockade of this pathway leads to inhibition of cytokine
production.40 Moreover, studies in a different
experimental system have shown that although production of IL-2 and
IFN- is blocked in anergizing MLR cultures, production of IL-10 is
augmented.41 Therefore, we examined the expression of
cytokines at various time intervals of our MLR cultures. Because the
functional characteristics of anergic cells are identified on
rechallenge, expression of cytokines was also assessed during
rechallenge (secondary) cultures. Blockade of the B7/CD28 pathway with
the combination of anti-B7-1 plus anti-B7-2 mAbs during primary MLR
resulted in dramatic inhibition of IL-2, IL-4, and IFN- production
in both primary and secondary cultures (Figure
2A,B). In contrast, addition of
anti-B7-1 plus anti-B7-2 mAbs during primary MLR resulted in
increased production of IL-10. Although there was only a slight
increase in IL-10 levels during primary culture in the presence of
anti-B7-1 plus anti-B7-2 mAbs (Figure 2A), there was a dramatic
increase in IL-10 levels in rechallenge, secondary cultures of cells
that had been treated with anti-B7 mAbs during primary MLR (Figure 2B).
TGF- was not detected in any of the conditions of primary or
secondary MLR cultures (data not shown). The observation that IL-4
production was inhibited by blockade of B7-mediated costimulation with
anti-B7 mAbs provides an explanation for the lack of significant
down-regulation of CD32 and CD64 on macrophages isolated from
anergizing cultures. IL-4 is the critical factor that mediates
down-regulation of CD32 and CD64, and this effect is counteracted by
IFN-![]() .21 Therefore, the presence of IFN- in
priming cultures in medium prevents IL-4-mediated down-regulation of
these receptors, whereas in anergizing cultures, none of these
cytokines is present to mediate an effect.
It has been proposed that IL-10 leads to the generation of
AAM
AMAC-1 is a cytokine closely related to MIP-1 AAM were detected in CD14+ cells isolated
from anergizing MLR cultures. Previous studies have shown that although
AAM have reduced capacity to process antigens, they have increased
phagocytotic activity.32,38 To determine whether
macrophages isolated from anergizing cultures had gained this
functional feature of AAM , we examined their phagocytotic ability.
CD14+ cells were isolated by positive selection from viable
responder PBMCs and were incubated with FITC-dextran for various time
intervals. Subsequently, endocytotic capacity of macrophages was
determined by flow cytometry. As shown in Figure
4A, macrophages isolated from cultures
treated with anti-B7-1 plus anti-B7-2 mAbs showed 4 times greater
endocytosis of FITC-dextran as compared with cells isolated from
priming cultures in medium alone or with control mAb (data not shown).
Increased phagocytotic capacity was also observed when CTLA4-Ig was
used instead of anti-B7-1 plus anti-B7-2 mAbs in anergizing MLR
cultures (data not shown).
Intracellular processing of phagocytosed antigen requires enzymatic
activation of nitric oxide reductase, which subsequently generates NO
and O2.42 It has been shown that although
AAM To determine the in vivo biologic significance of these findings, we examined whether macrophages in priming and anergizing culture conditions might have differential phagocytotic ability against cell populations in the MLR culture. CFSE-labeled responder PBMCs were cultured with unlabeled allogeneic stimulators. This approach allowed us to discriminate these 2 populations and to follow the fate of each one during culture. Strikingly, culture in the presence of anti-B7-1 plus anti-B7-2 mAbs or with CTLA4-Ig resulted in a significant decrease of the unlabeled (CFSE-negative) stimulator cells as compared with those detected in cultures with medium alone (Figure 4C). This event became detectable after 3 days of culture and was further augmented by day 7. This observation indicates that a higher degree of scavenging and clearance of the unlabeled (CFSE-negative) stimulator cells occurred in anergizing culture conditions. As mentioned earlier, previous studies have shown that AAM IL-10 has an active role in the generation of AAM .13,32 To examine whether IL-10 might be responsible for the enhanced phagocytotic activity observed in macrophages isolated from anergizing cultures, we added
anti-IL-10 neutralizing mAb in anergizing MLR cultures treated with
anti-B7-1 plus anti-B7-2 mAbs. Culture under these conditions significantly reduced the phagocytotic capacity of macrophages as
determined by FITC-dextran uptake (Figure 4A). Moreover, anti-IL-10 neutralizing mAb increased the levels of NO produced in the culture treated with anti-B7-1 plus anti-B7-2 mAbs (Figure 4B). Thus, IL-10
mediates at least one mechanism involved in the generation of
macrophages with increased phagocytotic capacity in anergizing MLR
cultures. Taken together, all of these results strongly suggest that
during induction of T-cell anergy by blockade of the B7/CD28 pathway, a
distinct activation program is initiated in macrophages, leading to
immunophenotypic and functional properties of AAM .
Differential gene expression in macrophages isolated from anergizing and priming cultures To examine whether AAM that were generated in anergizing MLR
cultures had differential expression of other macrophage-specific genes
as compared with CAM generated in priming cultures, we performed
suppression subtractive hybridization using PCR-select cDNA
subtraction. RNA was extracted from CD14+ cell populations
isolated from anergizing and priming cultures, and cDNA was prepared by
RT-PCR. cDNA from cells isolated from anergizing cultures was used as
"tester" and cDNA from priming cultures was used as "driver"
cDNA, and suppression subtractive hybridization was performed as
described in "Materials and methods."34 After a
subtracted cDNA library was obtained, confirmation that individual
clones were indeed differentially expressed was done by differential
screening, using as probes either cDNA prepared from anergizing
cultures (forward probe) or cDNA prepared from priming cultures
(reverse probe). This approach allows the identification of genes in
the subtracted library that are selectively detected by the forward
probe and therefore are selectively expressed in the cDNA population
isolated from anergizing cultures.
Among 200 recombinant clones tested, 11 clones represented genes that
were selectively or differentially expressed in macrophages isolated
from anergizing cultures (data not shown). Here, we present a number of
genes related to previously determined functional properties on
macrophages. Two receptors with known scavenging activity were
selectively expressed on macrophages isolated from anergizing cultures:
macrophage mannose receptor and sortilin. Macrophage mannose receptor was previously identified as a marker of
alternative immunologic macrophage activation.15 This is an important phagocytotic receptor mediating binding and ingestion of
microorganisms with surface mannose residues and soluble
mannose-containing glycoproteins. In fact, it has been reported that
macrophage mannose receptor has the most important role in mediating
endocytosis and scavenging by macrophages. It is expressed in alveolar
macrophages, and its expression is increased by steroids and inhibited
by IFN- Besides these 2 receptors, which are directly linked to the phagocytic
and scavenging properties of macrophages, a number of genes previously
associated with the maturation and differentiation program of monocytes
were differentially expressed between macrophages isolated from
anergizing and from priming MLR cultures. These results provide molecular evidence that distinct activation and differentiation gene programs are initiated on macrophages during anergizing and priming culture conditions. These distinct gene programs result in distinct functional properties of macrophages. Macrophages isolated from anergizing MLR cultures mediate suppression of T-cell responses Previous studies have shown that APCs generated in the presence of IL-10 do not induce T-cell responses but are rather immunosuppressive.25,32,38,39 To examine whether AAM
generated in anergizing cultures have immunosuppressive properties, we
isolated CD14+ cells from anergizing and priming cultures
by positive selection. These CD14+ cells were subsequently
added in a new primary MLR culture and in a secondary MLR culture of
purified CD4+ original responder cells and original PBMC
stimulators. CD14+ cells isolated from anergizing primary
cultures, which have phenotypic, functional, and molecular properties
of AAM , reduced alloresponses of CD4+ original responder
cells in a new primary MLR culture (Figure 5A) and in a secondary MLR culture
(Figure 5B). This inhibitory effect was dose dependent (data not
shown). Moreover, AAM also reduced alloresponses in primary and
secondary MLR cultures of different responder CD4+ cells
(data not shown). In contrast, CD14+ cells isolated from
priming cultures in medium alone, which have phenotypic and molecular
properties of CAM , augmented primary and secondary MLR responses of
original CD4+ responder cells (Figure 5A,B). These CAM
also augmented primary and secondary responses of different
CD4+ responder cells (data not shown).
T cells play a central role in the generation of GVHD after ABMT. Although T cells are mediators of immunity, their function is under the control of APCs. Therefore, APCs may regulate the activation of host-specific donor T cells, which are responsible for the generation of GVHD. Our present results show that blockade of the B7/CD28 pathway in anergizing priming MLR cultures leads to a distinct program of activation and differentiation of monocytes into macrophages, which acquire distinct gene expression and functional properties as compared with macrophages generated in MLR cultures in medium alone. This altered macrophage differentiation program closely resembles what has been defined as "alternative activation of antigen-presenting cells."13,14 Macrophages isolated from anergizing cultures have increased expression of CD14, MHC class II, CD23, and scavenger receptors and increased phagocytotic activity, but reduced ability to process and present antigen. Moreover, these macrophages mediate immunosuppressive effects to T cells. In our recent clinical trial that allowed successful haploidentical
BMT, recipient PBMCs were collected, irradiated, and cocultured with
donor bone marrow ex vivo in the presence of CTLA4-Ig to block B7-1-
and B7-2-mediated costimulation, washed, and infused into the
patient.8 All treated patients rapidly achieved
engraftment and developed full donor chimerism and no clinically
detectable GVHD. Although in vitro analysis during that study indicated
that anergy had been induced to host-specific donor T cells, our
present results indicate that additional mechanisms may be responsible for the clinical outcome of this treatment. As we show here, anergizing cultures result in the generation of AAM The cytokine profile of the anergic cells is characterized by defective
production of IFN- An additional mechanism responsible for the generation of AAM Several studies have shown an important role of IL-10 in the regulation
of the differentiation and activation program of
APCs.13,32,38 IL-10 prevents the differentiation of
monocytes to dendritic cells and promotes their maturation into
macrophages.32 These macrophages that develop in the
presence of IL-10 have increased endocytotic activity but defective
ability for antigen presentation. Although IL-10 blocks the
differentiation of CD14+ monocytes to dendritic cells
induced by granulocyte macrophage colony-stimulating factor and IL-13,
the macrophages that develop under these conditions have cytochemical
and phenotypic features of mature macrophages. Thus, the presence of
IL-10 does not simply prevent activation of monocytes, but initiates an
activation program that preferentially leads to their differentiation
into mature macrophages instead of dendritic cells. Our present studies
show that the defective ability of macrophages differentiated in the presence of IL-10 to induce T-cell activation is linked to their defective ability to process and present antigen. At the same time,
AAM Consistent with these functional findings, biochemical evidence from another study supports the notion that IL-10 does not simply deactivate monocytes, but leads to activation of selective signaling pathways.55 IL-10 blocks LPS-mediated activation of p56lyn, phosphorylation of vav, and activation of Ras in monocytes, but does not inhibit p56lyn-mediated induction of c-jun and c-fos.55 Thus, selective predominance of signaling pathways during monocyte activation in the presence of IL-10 results in distinct gene transcription and distinct functional properties. These developing observations about the significance of the distinct differentiation programs of APCs in the regulation of the immune response13,48 may have important implications in the field of transplantation. Clinical data and results from in vivo animal models have shown that allografts of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) have an unexpected immunologic behavior.56,57 Transplantation of allogeneic G-CSF-mobilized PBSCs, which contain 10-fold higher numbers of T cells as compared with bone marrow grafts, did not result in a higher incidence of GVHD.58,59 Moreover, such grafts achieved better engraftment across the HLA barrier.60,61 Potentially, CD14+ cells contained in the G-CSF-mobilized PBMCs have an active role in the reduced responsiveness of the CD4+ cells contained in this population.62 These CD14+ cells are involved in the impaired transactivation of the CD28 response element (CD28RE) of G-CSF-mobilized CD4+ cells.63 It was shown that such CD14+ cells produce high levels of IL-10 and mediate their effects in an IL-10-dependent manner.64 Studies in animal models have indicated that T cells from
G-CSF-treated animals preferentially produce IL-4 and IL-10 and are
associated with diminished ability to induce GVHD.57,65 Consistent with these experimental data, G-CSF-mobilized PBSCs from
healthy donors contain high numbers of type-2 dendritic cells (DC2),
which prime T cells to produce IL-4 and IL-10.66
Interestingly, umbilical cord blood, another source of allogeneic stem
cells for transplantation associated with a low incidence of acute
GVHD, contains DC2 and not DC1-type cells.67 These studies
suggest that donor APCs regulate both GVHD induction and engraftment
and have a critical role in the clinical outcome of allogeneic
transplantation. Consistent with these observations, in our system
IL-10 was produced by CD4+ and not by CD14+
cells. Moreover, our experiments showed a reciprocal regulation between
T cells and macrophages. Anergic T cells generated during blockade of
B7/CD28 interaction produce high amounts of IL-10, which mediates
generation of AAM An additional interesting finding of our study with potential clinical
significance is the observation that blockade of B7/CD28 interactions
leads to the generation of AAM In conclusion, our results show that induction of T-cell anergy by
blockade of B7/CD28 costimulation influences the maturation and
differentiation process of macrophages, which subsequently have an
inhibitory role on T-cell responses. This novel and unexpected observation that anergic T cells mediate the generation of AAM
Submitted August 7, 2001; accepted October 11, 2001.
Supported by National Institutes of Health grants AI 43552, AI 41584, and HL 54785.
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: Vassiliki A. Boussiotis, Dana-Farber Cancer Institute, Mayer 547, 44 Binney St, Boston, MA 02115; e-mail: vassiliki_boussiotis{at}dfci.harvard.edu.
1. Ferrara JLM, Deeg HJ. Mechanisms of disease. Graft-versus-host disease. N Engl J Med. 1991;324:667-674[Medline] [Order article via Infotrieve].
2.
Kernan NA, Bartsch G, Ash RC, et al.
Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program.
N Engl J Med.
1993;328:593-602
3.
Lin H, Bolling SF, Linsley P, et al.
Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.
J Exp Med.
1993;178:1801-1806
4.
Blazar BR, Taylor PA, Linsley PS, Vallera PA.
In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice.
Blood.
1994;83:3815-3825
5.
Kirk AD, Harlan DM, Armstrong NN, et al.
CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates.
Proc Natl Acad Sci U S A.
1997;94:8789-8794 6. Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature. 1996;381:434-438[CrossRef][Medline] [Order article via Infotrieve]. 7. Sun H, Subbotin V, Chen C, et al. Prevention of chronic rejection in mouse aortic allografts by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody. Transplantation. 1997;64:1838-1843[CrossRef][Medline] [Order article via Infotrieve].
8.
Guinan EC, Boussiotis VA, Neuberg D, et al.
Transplantation of anergic histoincompatible bone marrow allografts.
N Engl J Med.
1999;340:1704-1714 9. Schwartz RH. T cell clonal anergy. Curr Opin Immunol. 1997;9:351-357[CrossRef][Medline] [Order article via Infotrieve].
10.
Boussiotis VA, Barber DL, Nakarai T, et al.
Prevention of T cell anergy by signaling through the 11. Boussiotis VA, Freeman GJ, Gribben JG, Nadler LM. The role of B7-1/B7-2:CD28 /CTLA-4 pathways in the prevention of anergy, induction of productive immunity and down-regulation of the immune response. Immunol Rev. 1996;153:5-26[CrossRef][Medline] [Order article via Infotrieve]. 12. Takahashi K, Naito M, Takeya M. Development and heterogeneity of macrophages and their related cells through their differentiation pathways. Pathol Int. 1996;46:473-485[Medline] [Order article via Infotrieve]. 13. Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity. 1999;10:137-142[CrossRef][Medline] [Order article via Infotrieve]. 14. Goerdt S, Politz O, Schledzeqwski K, et al. Alternative versus classical activation of macrophages. Pathobiology. 1999;67:222-226[CrossRef][Medline] [Order article via Infotrieve].
15.
Stein M, Keshav S, Harris N, Gordon S.
Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation.
J Exp Med.
1992;176:287-292 16. Mosser DM, Handman E. Treatment of murine macrophages with interferon-gamma inhibits their ability to bind leishmania promastigotes. J Leukoc Biol. 1992;52:369-376[Abstract]. 17. Geng Y-J, Hansson GK. Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest. 1992;89:1322-1330.
18.
Hogger P, Dreier J, Droste A, Buck F, Sorg C.
Identification of the integral membrane protein RM3/1 on human monocytes as a glucocorticoid-inducible member of the scavenger receptor cysteine-rich family (CD163).
J Immunol.
1998;161:1883-1890 19. Devitt A, Moffat OD, Raykandalia C, Capra JD, Simmons DL, Gregory CD. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature. 1998;392:505-509[CrossRef][Medline] [Order article via Infotrieve]. 20. Gregory CD. CD14-dependent clearance of apoptotic cells: relevance to the immune system. Curr Opin Immunol. 2000;12:27-34[CrossRef][Medline] [Order article via Infotrieve]. 21. Becker S, Daniel EG. Antagonistic and additive effects of IL-4 and interferon-gamma on human monocytes and macrophages: effects on Fc receptors, HLA-D antigens and superoxide production. Cell Immunol. 1990;129:351-362[CrossRef][Medline] [Order article via Infotrieve].
22.
Munder M, Eichmann K, Modolell M.
Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype.
J Immunol.
1998;160:5347-5354
23.
Kodelja V, Muller C, Politz O, Hakij N, Orfanos CE, Goerdt S.
Alternative macrophage activation-associated CC-chemockine-1, a novel structural homologue of macrophage inflammatory protein-1 alpha with a Th2-associated expression pattern.
J Immunol.
1998;160:1411-1418 24. Adema GJ, Hartgers F, Verstraten R, et al. A dendritic-cell-derived C-C chemokine that preferentially attracts naive T cells. Nature. 1997;387:713-717[CrossRef][Medline] [Order article via Infotrieve]. 25. Schebesch C, Kodelja V, Muller C, et al. Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro. Immunology. 1997;92:478-486[CrossRef][Medline] [Order article via Infotrieve].
26.
Chang M, Pollard JW, Khalili H, Goyert SM, Diamond B.
Mouse placental macrophages have a decreased ability to present antigen.
Proc Natl Acad Sci U S A.
1993;90:462-466 27. Mues B, Langer D, Zwadlo G, Sorg C. Phenotypic characterization of macrophages in human term placenta. Immunology. 1989;67:303-307[Medline] [Order article via Infotrieve].
28.
Holt PG, Schon-Hegard MA, Oliver J.
MHC class II antigen-bearing dendritic cells in pulmonary tissues of the rat. Regulation of antigen presentation activity by endogenous macrophage population.
J Exp Med.
1988;167:262-274 29. Song E, Ouyang N, Horbelt M, Antus B, Wang M, Exton MS. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol. 2000;204:19-28[CrossRef][Medline] [Order article via Infotrieve]. 30. Boussiotis VA, Tsai E, Yunis EJ, et al. IL-10 producing T cells suppress immune responses in anergic tuberculosis patients. J Clin Invest. 2000;105:1317-1324[Medline] [Order article via Infotrieve].
31.
Boussiotis VA, Freeman GJ, Gribben JG, Daley J, Gray G, Nadler LM.
Activated human B lymphocytes express three CTLA4 binding counter-receptors which costimulate T cell activation.
Proc Natl Acad Sci U S A.
1993;90:11059-11063 32. Allavena P, Piemonti L, Longoni D, et al. IL-10 prevents the differentiation of monocytes to dendritic cells but promotes their maturation to macrophages. Eur J Immunol. 1998;28:359-369[CrossRef][Medline] [Order article via Infotrieve]. 33. Freeman GJ, Boussiotis VA, Anumanthan A, et al. B7-1 and B7-2 do not deliver identical costimulatory signals since B7-2 but not B7-1 preferentially costimulates the initial production of IL-4. Immunity. 1995;2:523-532[CrossRef][Medline] [Order article via Infotrieve].
34.
Diatchenko L, Lau Y-FC, Campbell AP, et al.
Suppression subtractive hybridization: a method for generating differentially regulated or tissue-specific cDNA probes and libraries.
Proc Natl Acad Sci U S A.
1996;93:6025-6030
35.
Gribben JG, Guinan EC, Boussiotis VA, et al.
Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool.
Blood.
1996;87:4887-4893
36.
Freedman AS, Freeman GJ, Rhynhart K, Nadler LM.
Selective induction of B7/BB-1 on interferon-
37.
Freeman GJ, Gribben JG, Boussiotis VA, et al.
Cloning of B7-2: a CTLA4 counter-receptor that costimulates human T cell proliferation.
Science.
1993;262:909-911 38. Morel A-S, Quaratino S, Douek DC, Londei M. Split activity of interleukin-10 on antigen capture and antigen presentation by human dendritic cells: definition of a maturation step. Eur J Immunol. 1997;27:26-34[Medline] [Order article via Infotrieve]. 39. Koppelman B, Neefjes JJ, de Vries JE, de Waal Malefyt R. Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity. 1997;7:861-871[CrossRef][Medline] [Order article via Infotrieve].
40.
Thompson CB, Lindsten T, Ledbetter JA, et al.
CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines.
Proc Natl Acad Sci U S A.
1989;86:1333-1337 41. Van Gool SW, Vermeiren J, Rafiq K, Lorr K, de Boer M, Ceuppens JL. Blocking CD40-CD154 and CD80/CD86-CD28 interactions during primary allogeneic stimulation results in T cell anergy and high IL-10. Eur J Immunol. 1999;29:2367-2375[CrossRef][Medline] [Order article via Infotrieve]. 42. Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992;6:3051-3064[Abstract].
43.
Nielsen MS, Jacobsen C, Olivecrona G, Gliemann J, Petersen CM.
Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase.
J Biol Chem.
1999;274:8832-8836
44.
Brugger W, Reinhardt R, Galanos C, Andreesen R.
Inhibition of in vitro differentiation of human monocytes to macrophages by lipopolysaccharides (LPS): phenotypic and functional analysis.
Int Immunol.
1991;3:221-227 45. Ganter U, Bauer J, Majello B, Gerok W, Ciliberto G. Characterization of mononuclear-phagocyte terminal maturation by mRNA phenotyping using a set of cloned cDNA probes. Eur J Biochem. 1989;185:291-296[Medline] [Order article via Infotrieve]. 46. Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T cell responses and prevents colitis. Nature. 1997;389:737-742[CrossRef][Medline] [Order article via Infotrieve]. 47. Boise LH, Minn AJ, Noel PJ, et al. CD28 costimulation can promote T cell survival by enhancing the expression of bcl-xL. Immunity. 1995;3:87-98[CrossRef][Medline] [Order article via Infotrieve].
48.
Steinman RM, Turley S, Mellman I, Inaba K.
The induction of tolerance by dendritic cells that have captured apoptotic cells.
J Exp Med.
2000;191:411-416
49.
Sauter B, Albert ML, Francisco L, Larsson M, Somersan S, Bhardwaj N.
Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells.
J Exp Med.
2000;191:423-434
50.
Huang F-P, Platt N, Wykes M, et al.
A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph codes.
J Exp Med.
2000;191:435-443 51. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101:890-898[Medline] [Order article via Infotrieve].
52.
Gao Y, Herndon JM, Zhang H, Griffin TS, Ferguson TA.
Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis.
J Exp Med.
1998;188:887-896
53.
Freeman GJ, Long AJ, Iwai Y, et al.
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
J Exp Med.
2000;192:1027-1034 54. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-I and inhibits T cell activation. Nat Immunol. 2001;2:261-268[CrossRef][Medline] [Order article via Infotrieve].
55.
Geng Y, Gulbins E, Altman A, Lotz M.
Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway.
Proc Natl Acad Sci U S A.
1994;91:8602-8606 56. Ballin A, Sagi O, Schiby G, Meytes D. Improved survival and marrow engraftment of mice transplanted with bone marrow of GM-CSF-treated donors. Eur J Haematol. 1993;50:168-171[Medline] [Order article via Infotrieve]. 57. Talmadge JE, Reed EC, Kessinger A, et al. Immunologic attributes of cytokine mobilized peripheral blood stem cells and recovery following transplantation. Bone Marrow Transplant. 1996;17:101-109[Medline] [Order article via Infotrieve].
58.
Bensinger WI, Weaver CH, Appelbaum FR, et al.
Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor.
Blood.
1995;85:1655-1658
59.
Bensinger WI, Martib PJ, Stromer B, et al.
Transplantation of bone marrow as compared with peripheral blood cells from HLA-identical relatives with patients with hematologic cancers.
N Engl J Med.
2001;344:175-181
60.
Beelen DW, Ottinger HD, Elmaagacli A, et al.
Transplantation of filgrastim-mobilized peripheral blood stem cells from HLA-identical siblings or alternative family donors in patients with hematological malignancies: a prospective comparison on clinical outcome, immune reconstitution and hematopoietic chimerism.
Blood.
1997;90:4725-4735
61.
Aversa F, Tabilio A, Velardi A, et al.
Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.
N Engl J Med.
1998;339:1186-1193
62.
Mielcarek M, Martin PJ, Torok-Storb B.
Suppression of alloantigen-induced T cell proliferation by CD14+ cells derived from granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells.
Blood.
1997;89:1629-1634
63.
Tanaka J, Mielcarek M, Torok-Storb B.
Impaired induction of the CD28-responsive complex in granulocyte colony-stimulating factor mobilized CD45 T cells.
Blood.
1998;91:347-352
64.
Mielcarek M, Graf L, Johnson G, Torok-Storb B.
Production of interleukin-10 by granulocyte colony-stimulating factor-mobilized blood products: a mechanism for monocyte-mediated suppression of T-cell proliferation.
Blood.
1998;92:215-222
65.
Pan L, Delmore BA, Ferrara JLM.
Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease.
Blood.
1995;86:4422-4429 66. Arpinati M, Green CL, Heimfeld S, Heuser JE, Anasetti C. Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood. 2000;15:2484-2490.
67.
Sorg RV, Kogler G, Wernet P.
Identification of cord blood dendritic cells as an immature CD11c
68.
Kennedy DW, Abkowitz JL.
Mature monocytic cells enter tissues and engraft.
Proc Natl Acad Sci U S A.
1998;95:14944-14949
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
![]() |
S. Fruchon, M. Poupot, L. Martinet, C.-O. Turrin, J.-P. Majoral, J.-J. Fournie, A.-M. Caminade, and R. Poupot Anti-inflammatory and immunosuppressive activation of human monocytes by a bioactive dendrimer J. Leukoc. Biol., March 1, 2009; 85(3): 553 - 562. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Fehr, S. Wang, F. Haspot, J. Kurtz, P. Blaha, T. Hogan, M. Chittenden, T. Wekerle, and M. Sykes Rapid Deletional Peripheral CD8 T Cell Tolerance Induced by Allogeneic Bone Marrow: Role of Donor Class II MHC and B Cells J. Immunol., September 15, 2008; 181(6): 4371 - 4380. [Abstract] [Full Text] [PDF] |
||||
![]() |
A.-S. Dugast, T. Haudebourg, F. Coulon, M. Heslan, F. Haspot, N. Poirier, R. Vuillefroy de Silly, C. Usal, H. Smit, B. Martinet, et al. Myeloid-Derived Suppressor Cells Accumulate in Kidney Allograft Tolerance and Specifically Suppress Effector T Cell Expansion J. Immunol., June 15, 2008; 180(12): 7898 - 7906. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Kriegel, S. Adam-Klages, C. Gabler, N. Blank, M. Schiller, C. Scheidig, J. R. Kalden, and H.-M. Lorenz Anti-HLA-DR-triggered monocytes mediate in vitro T cell anergy Int. Immunol., April 1, 2008; 20(4): 601 - 613. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. Honstettre, S. Meghari, J. A. Nunes, H. Lepidi, D. Raoult, D. Olive, and J.-L. Mege Role for the CD28 Molecule in the Control of Coxiella burnetii Infection Infect. Immun., March 1, 2006; 74(3): 1800 - 1808. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Papasavvas, J. Sun, Q. Luo, E. C. Moore, B. Thiel, R. R. MacGregor, A. Minty, K. Mounzer, J. R. Kostman, and L. J. Montaner IL-13 Acutely Augments HIV-Specific and Recall Responses from HIV-1-Infected Subjects In Vitro by Modulating Monocytes J. Immunol., October 15, 2005; 175(8): 5532 - 5540. [Abstract] [Full Text] [PDF] |
||||
![]() |
E. Schutyser, A. Richmond, and J. Van Damme Involvement of CC chemokine ligand 18 (CCL18) in normal and pathological processes J. Leukoc. Biol., July 1, 2005; 78(1): 14 - 26. [Abstract] [Full Text] [PDF] |
||||
![]() |
T. Kezuka, M. Takeuchi, H. Keino, Y. Usui, A. Takeuchi, N. Yamakawa, and M. Usui Peritoneal Exudate Cells Treated with Calcitonin Gene-Related Peptide Suppress Murine Experimental Autoimmune Uveoretinitis via IL-10 J. Immunol., July 15, 2004; 173(2): 1454 - 1462. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Guillot, S. Menoret, C. Guillonneau, C. Braudeau, M. G. Castro, P. Lowenstein, and I. Anegon Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig Blood, April 15, 2003; 101(8): 3325 - 3333. [Abstract] [Full Text] [PDF] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||