By
From the * Department of Oncology and the Department of Cardiology, Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205; and the § Department of Pediatrics,
Washington University School of Medicine, St. Louis, Missouri 63110
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Abstract |
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The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8+ cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.
Key words: cancer; vaccine; T helper cell; macrophage; eosinophil ![]() |
Introduction |
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The exquisite specificity of antigen recognition by the T cell arm of the immune response provides an important basis for cancer immunotherapy. The ability to discriminate tumor cells from normal tissues is critical for enabling effective tumor destruction while minimizing toxicity. Indeed, the isolation of tumor-specific T cells from cancer patients has fueled the search for tumor-associated antigens. The molecular identification of several such antigens, particularly in human melanoma, has enabled the pursuit of vaccine strategies that specifically target defined tumor antigens (1).
In the setting where relevant tumor rejection antigens have yet to be defined, vaccination with modified whole tumor cells as the antigen source has been explored as a means to prime systemic antitumor immunity. The host response to this form of vaccination has been shown to be significantly enhanced when the immunizing tumor cells are transduced with genes encoding cytokines or other molecules involved in the regulation of immune responses (4). For both tumor cell-based and defined antigen vaccine strategies, T cell subset depletion studies have usually demonstrated the requirement for both CD4+ and CD8+ T cells for systemic tumor rejection to occur.
Given that most nonhematopoietic tumors express MHC class I molecules, which serve as the restricting element for CD8+ T cell recognition, but do not express MHC class II molecules, which are required for CD4+ T cell recognition, it has been assumed that the predominant tumoricidal effector mechanism is killing by CD8+ CTL. The requirement for CD4+ T cells in these responses has been attributed to providing help during priming to achieve full activation and effector function of tumor-specific CTL. Indeed, MHC class I restricted CD8+ T cells that specifically lyse tumor cells in vitro are frequently measured to document vaccine efficacy and to serve as a surrogate end point in clinical tumor vaccine trials.
However, several lines of evidence suggest a broader role for CD4+ T cells in mediating other significant antitumor effector functions. First, studies in which mice were vaccinated several weeks before a live tumor challenge demonstrated that although immunologically intact mice were able to reject tumor, the depletion of CD4+ T cells with a mAb just before the tumor challenge resulted in the complete loss of tumor rejection (5). In these experiments, T cell help for CTL priming was fully available at the time of vaccination. This outcome suggests that CD4+ T cells play a more direct role in the effector phase of tumor rejection. Second, we have demonstrated previously that vaccination against tumor cells completely lacking MHC class I expression resulted in tumor rejection that was comparable to that seen against a challenge with an MHC class I positive variant of the same tumor (6). Depletion of either CD4+ T cells or NK cells, but not CD8+ T cells, resulted in the inability to reject the MHC class I negative variant, suggesting that CD4+ T cells may provide help as well as a measure of antigen specificity to effector cells of the immune response that do not themselves have the capacity for antigen-specific recognition.
To dissect the mechanism of CD4+ T cell effector function during tumor rejection, we studied immune responses induced by a genetically modified whole cell vaccine. A comparison of genetically modified whole cell vaccines, using the B16 melanoma (7) transduced with a large set of individual cytokine genes, demonstrated that GM-CSF- transduced vaccines generated potent and long-lasting systemic antitumor immunity that was dependent on both CD4+ and CD8+ T cells (5). Induction of immunity against the poorly immunogenic B16 tumor appears to be due to the ability of the locally produced GM-CSF to activate bone marrow-derived APCs during the priming phase to process and present tumor antigens to both CD4+ and CD8+ T cells (8). In the following studies, we were able to demonstrate that rather than simply providing help for CD8+ T cells, CD4+ T cells express both Th1 and Th2 cytokines and recruit other antitumor effector cells in addition to CD8+ T cells.
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Materials and Methods |
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In Vivo Vaccination: Tumor Challenge Experiments.
6-8-wk-old female C57BL/6 mice were obtained from the National Cancer Institute (Bethesda, MD) and housed in the Johns Hopkins Oncology Center Animal Facility. In the same facility, CD4Quantitative RT-PCR.
TRIZOL (GIBCO BRL, Gaithersburg, MD) was used to extract total RNA from lymphocytes draining the site of s.c. vaccination with irradiated B16-GM-CSF and from the site of s.c. challenge with live B16-WT cells. The SUPERSCRIPT Preamplification System (GIBCO BRL) was used to reverse transcribe total RNA to cDNA. The cDNA and cytokine competitor (a gift from Dr. Richard Locksley, University of California San Francisco, San Francisco, CA) were then PCR amplified forImmunohistochemistry for iNOS.
The biopsy of the tumor challenge site was removed and flash frozen in O.C.T. compound (Sakura Finetek USA, Inc., Torrance, CA) and dry-ice cooled isopentane. 5-µm tissue sections were fixed for 10 min in acetone and washed with TBS. Sections were quenched with a solution of 0.05% H2O2, 1% normal goat serum, and 0.5% milk for 30 min and then blocked with TBS/milk/1% normal goat serum for 10 min. The sections were then incubated with either ![]() |
Results |
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Wild-type, CD4 knockout
(CD4/
) (12) and CD8 knockout (CD8
/
) mice (13) were
vaccinated subcutaneously in the left flank with 106 irradiated
B16-GM-CSF (B16 cells transduced with GM-CSF) and challenged 2 wk later in the right flank with 105 wild-type
(nontransduced) B16 melanoma cells. This dose of wild-type B16 cells is roughly 100-fold greater than the minimum dose
that forms tumors in nonvaccinated C57BL/6 wild-type
mice, but is rejected in the majority of animals previously
vaccinated with B16-GM-CSF. In contrast to vaccinated
wild-type mice, immunization of CD4
/
mice failed to
prime a systemic immune response capable of rejecting this tumor challenge (Fig. 1). Interestingly, although similarly immunized CD8
/
mice (13) are impaired in their
ability to reject this tumor challenge, a significant fraction
of CD8
/
mice mounted a successful tumor rejection. In
several experiments over a range of tumor challenge doses,
the fraction of immunized CD8
/
mice that rejected a tumor challenge was roughly half of that observed in immunized wild-type mice (data not shown). In contrast, no
measurable antitumor responses were ever demonstrated in
CD4
/
mice. These observations directly demonstrate the
existence of other CD4+ T cell-dependent effector mechanisms besides MHC class I restricted CD8+ CTL.
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The best characterized function of CD4+ T cells is the elaboration of cytokines that
regulate downstream effector function of both cellular and
humoral immunity. The division of CD4+ T cell or Th
function into Th1 and Th2 phenotypes originally was
based on the observation that murine T helper clones produced certain cytokines in a mutually exclusive fashion
(14). Subsequent studies indicated that Th1 cytokines,
such as -IFN, as well as cytokines that promote Th1 differentiation, such as IL-12, inhibit Th2 development (17-
19), whereas Th2 cytokines, such as IL-4 and IL-10, inhibit
Th1 development (20). Taken together, these findings
suggested that productive in vivo Th responses would develop uniquely along either a Th1 or a Th2 pathway and
that the ensuing immunologic effector mechanisms would
reflect the distinct pattern of cytokine production associated with the particular pathway of Th differentiation.
We used the B16 vaccination-challenge system to evaluate the expression of -IFN, the prototypical Th1 cytokine, and IL-4, the prototypical Th2 cytokine at the site of
tumor challenge. Competitive quantitative PCR analysis of
-IFN and IL-4 mRNA at the site of tumor challenge
demonstrated that both of these messages were significantly
increased, relative to naive mice (Fig. 2 A). The increase in
-IFN and IL-4 mRNA was similar in vaccinated CD8
/
mice to that observed in wild-type mice. In contrast,
-IFN and IL-4 mRNA were not increased at the tumor
challenge site in vaccinated CD4
/
mice, indicating that
both
-IFN and IL-4 production are dependent upon activated CD4+ T cells. These results contrast with the findings in other studies on immune responses to parasites and
intracellular bacteria that demonstrated that the production
of one or the other cytokine ultimately dominates the effector phase of the response, leading to a polarized pattern
of Th cytokine secretion that is associated with the ability
to clear the infection (23).
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To
determine whether the Th1 cytokine, -IFN, or the Th2
cytokine, IL-4, was required for the induction of systemic
antitumor immunity by B16-GM-CSF, vaccination-challenge experiments were performed in
-IFN
/
and
IL-4
/
mice (30, 31). As demonstrated in Fig. 2 B, protective immunity against B16 melanoma challenge was significantly decreased in both sets of cytokine gene knockout
mice. In the case of
-IFN
/
mice, protection against
tumor challenge was completely eliminated, whereas in
IL-4
/
mice, protection was reduced by ~50% relative to
vaccinated wild-type mice. Thus, in accordance with the
PCR results in Fig. 2 A, and in contrast to the immune response in previous infectious models, induction of maximal
systemic antitumor immunity was dependent on both the
Th1 and the Th2 components of the immune response.
To further define
potential downstream effector mechanisms mediating tumor rejection, tissue from the tumor challenge site was examined. As seen in Fig. 3, eosinophils are one of the most prominent infiltrating cell types at the site of tumor challenge in vaccinated mice (in addition to macrophages and
lymphocytes). Eosinophils represent a candidate Th2-dependent antitumor effector cell. Their differentiation from myeloid progenitors requires the Th2 cytokine IL-5 (32), and
their recruitment from the blood into tissues is partially dependent on IL-4 (33). Indeed, the dense eosinophil infiltrate at the tumor challenge site is reminiscent of that seen
in IL-4 transduced tumor cells after in vivo injection (34,
35). Eosinophils are completely absent from the tumor challenge site in vaccinated CD4/
mice and are ~80%
reduced in vaccinated IL-4
/
mice, indicating that CD4+
T cell-derived IL-4 is critical for their recruitment. In contrast, the challenge site of vaccinated CD8
/
and
-IFN
/
mice demonstrated an eosinophil infiltrate similar to that of wild-type mice.
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Several lines of evidence support the notion that the infiltrating eosinophils are important Th2 dependent antitumor effectors, rather than simply inactive bystanders. First,
protection against tumor challenge was significantly diminished in vaccinated IL-5/
mice (Fig. 2 B) (36). Because
IL-5 is critical for differentiation of bone marrow progenitors into eosinophils, mature eosinophils fail to develop in
IL-5
/
mice. Second and most importantly, the loss of
systemic antitumor immunity was associated with the absence of eosinophils at the tumor challenge sites in IL-5
/
mice (Fig. 3). Third, earlier studies of both mouse and human tissues revealed eosinophil degranulation at the tumor
site, as demonstrated by the presence of eosinophil granule
specific major basic protein in the interstitial space (37).
This degranulation is a characteristic feature of activated
eosinophils (38).
A number of potential antitumor effector mechanisms could depend on the Th1 component. The
majority of studies on antitumor immunity have focused on
CTL generation as the critical Th1-dependent effector
mechanism. We wished to examine whether the priming
of tumor-specific CTL was impaired in -IFN knockout
mice, which might account for the marked dependence of
successful tumor rejection on the ability to produce this cytokine. Interestingly, induction of CTL specific for an immunodominant MHC class I restricted B16 antigen derived
from the tyrosinase related protein-2 protein (39) was identical in wild-type, IL-4
/
, and
-IFN
/
mice (Fig. 4).
Although CTL induction was normal in the cytokine gene
knockout mice, tyrosinase related protein-2-specific CTL could not be detected in B16-GM-CSF vaccinated CD4
/
mice. This finding is consistent with recent reports that
have identified CD154/CD40 interactions between CD4+
T cells and APCs as mediators of T cell help for CTL priming via the cross-priming pathway (40). The fact that
there was not a loss of antitumor CTL activity associated
with the corresponding loss of in vivo tumor protection in
the cytokine gene knockout mice does not mean that CTL
are unimportant as antitumor effectors, but it does indicate
that CTL alone are insufficient to eliminate tumor challenges.
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Another potential Th1 effector mechanism is NO production
by iNOS in activated macrophages. NO production by
macrophages has been demonstrated to have tumoricidal
activity both in vitro and in vivo (43). Indeed, immunohistochemical staining at the challenge site of B16-GM-CSF vaccinated wild-type mice showed an abundant infiltration of macrophages (Fig. 5 B). This infiltrate was still
evident in the cytokine gene knockout mice, but was absent in CD4/
mice (Fig. 5 C). Infiltrating macrophages
stained strongly positive for iNOS in vaccinated wild-type
mice (Fig. 5 H). In contrast, despite the presence of large
numbers of macrophages in B16-GM-CSF vaccinated
-IFN
/
mice (Fig. 5 E), iNOS was virtually absent at the
challenge site in
-IFN
/
mice (Fig. 5 K). iNOS expression was present at the challenge site of IL-4
/
mice (Fig.
5 L), although levels were reduced relative to wild-type mice. The reduction in iNOS levels in IL-4
/
mice was
somewhat unexpected, given that IL-4 inhibits iNOS expression in macrophages (55). One possible explanation
for this reduction in IL-4
/
mice could be the compensatory hyperexpression of other cytokines, such as IL-10, that
indirectly inhibit iNOS expression through the inhibition
of TNF-
expression, a costimulator for iNOS induction (21, 22, 58). It is also possible that the decreased iNOS expression is secondary to the decreased tissue eosinophilia, as eosinophils themselves are known to express TNF-
(61, 62). Furthermore, eosinophils also express eosinophil
peroxidase and macrophage inflammatory protein-1, both
of which induce TNF-
release from macrophages (63,
64). Therefore, it is possible that eosinophils function as a
positive modulator for iNOS release by macrophages. Furthermore, the dramatic absence of iNOS expression in
-IFN
/
mice, which fail to reject tumor in response to
vaccination, suggests that NO production by tumor infiltrating macrophages may represent an important in vivo
antitumor effector mechanism.
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Direct functional evidence for the role of iNOS in tumor rejection was sought in vaccination-challenge experiments in iNOS/
mice. In accordance with the previous
immunohistochemical staining, vaccinated iNOS
/
mice
show a substantial decrease in protection against challenge with tumor (Table 1), thereby demonstrating the critical
role for NO in antitumor killing.
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Activated phagocytes can also mediate killing through
the production of superoxide, which is produced by the
NADPH oxidase-enzyme complex. Mutations in the CYBB
gene which encodes the 91-kD glycoprotein component of
the oxidase (gp91phox) account for the X-linked form of
chronic granulomatous disease, an immunodeficiency syndrome characterized by recurrent infections with catalase-positive microorganisms. Phagocytes from chronic granulomatous disease patients or genetic knockout mice of
gp91phox (X-CGD mice) (65) mount a severely defective
respiratory burst with little or no generation of superoxide or hydrogen peroxide. X-CGD mice immunized with
B16-GM-CSF showed a substantial decrease in protection
against challenge with B16 tumor (Table 1), thereby implicating superoxide in the antitumor response. The loss of
tumor protection in both the iNOS/
and X-CGD mice
indicates that both NO and superoxide involved in phagocytic killing play a major role in the antitumor effect induced by B16-GM-CSF.
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Discussion |
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Taken together, the experiments presented here demonstrate that effective antitumor immunity is critically dependent upon the CD4+ T cell, which is responsible for orchestrating multiple immunologic effector arms, dependent
on both Th1 and Th2 cytokines. We have demonstrated
previously that the priming phase of the immune response to GM-CSF-secreting tumor cells involves the recruitment
of bone marrow-derived APCs which process and present
tumor antigens to both CD4+ and CD8+ T cells (10). In
this study, we have examined the effector mechanisms required for the successful rejection of tumor found at distant
sites. As the challenge tumor used in these studies is MHC
class II negative, the effector phase of the response also requires processing of tumor antigens by infiltrating APCs for presentation to CD4+ T cells. These observations underscore the critical role of bone marrow-derived APCs in
two phases of the antitumor immune responsepriming of
de novo T cell responses (thought to be mediated largely
by activated dendritic cells) and amplification of the effector phase through the processing and presentation of tumor
antigen to memory CD4+ T cells. Through the local release of cytokines, these cells direct the effector response,
recruiting and activating tumoricidal macrophages, eosinophils, and the other populations seen histologically. This
cooperative interaction between APC and memory CD4+
T cell is the hallmark of a classic delayed type hypersensitivity response.
The requirement for CD4+ T cells in the effector phase of an immune response to tumors that do not themselves express MHC class II is consistent with earlier results in adoptive transfer systems. Infusion of tumor-specific CD4+ T cells was shown to be capable of eradicating the MHC class II negative FBL-3 murine leukemia line (66). Class II positive macrophages were found to be required to present processed tumor antigens to CD4+ T cells (67). Furthermore, several vaccine strategies that directly enhance the priming of tumor-specific CD4+ T cells have been shown to augment the systemic rejection of MHC class II negative tumors (68).
Previous studies in cancer immunology have focused largely on Th1 effector mechanisms, and particularly on CTL generation. Interestingly, CTL may play a smaller role in eradication of the B16 challenge tumor than in other cancer vaccine systems because of the expression of Fas ligand by B16 (as well as by many human melanomas), which may protect the tumor from direct CTL-mediated killing (72). Instead, it appears that both macrophages and eosinophils play a major role in the immune response against B16 and probably act together to achieve more efficient tumor killing. This is supported by previous studies showing that (a) eosinophil peroxidase can synergize with macrophage reactive oxygen intermediates to kill tumor cells (73) and (b) peroxidases can catalyze the oxidation of nitrite to generate further cytotoxic radicals (74). However, neither macrophages nor eosinophils have an intrinsic capacity for tumor specificity. Instead, the tumor specificity of these effectors is based on their activation by neighboring tumor-specific Th cells.
To date, the major effort in tumor antigen identification has focused almost exclusively on antigens recognized by tumor-specific, MHC class I restricted CTL. Several antigen-specific vaccine strategies incorporating class I restricted tumor antigens identified through these efforts are being explored currently in animal models and early phase clinical trials. In the absence of known MHC class II restricted tumor antigens, such strategies rely on the effects of adjuvants or incorporate surrogate class II antigens from infectious pathogens to provide help for CTL induction. The studies presented here suggest that although Th responses generated by this type of vaccination may enhance CTL induction during priming, they are unlikely to participate in the effector phase that requires tumor-specific CD4+ T cell help. Ultimately, the optimal tumor antigen-specific vaccine will ideally incorporate a panel of dominant tumor antigens recognized by both CD4+ and CD8+ T cells.
The finding that GM-CSF transduced whole cell vaccines simultaneously induce Th1 and Th2 differentiation
contrasts with previous findings of in vivo immune responses to both intracellular bacteria and parasites. In resistant mouse strains, such as C3H or C57BL/6, infection
with the intracellular parasite Leishmania major exclusively induces a Th1 response, characterized by high -IFN and
low IL-4 production (23). Furthermore, eradication of
L. major has been shown to be dependent upon
-IFN-
dependent stimulation of iNOS in macrophages (75).
Conversely, in susceptible mouse strains, such as BALB/c,
infection with L. major induces exclusively a Th2 immune
response, characterized by high IL-4 and low
-IFN production (23, 28, 85). Based upon this altered pattern of
Th differentiation and the direct inhibition of macrophage activation by IL-4 and IL-10 (22, 56, 60, 86), BALB/c mice fail to mount effective immunity against L. major
challenge. In contrast, protective immunity against helminth infections, such as Schistosoma mansoni and Nippostrogylus brasiliensis, is associated with Th2 development and
the induction of IL-4 (26, 27, 89).
In each of these models, the definitive demonstration
that particular Th1 or Th2 cytokines are critical in directing appropriate immune responses comes from the finding
that elimination of a given cytokine, either by in vivo antibody depletion or by genetic knockout, results in a loss of
protection against the particular pathogen. For example,
-IFN blockade renders formerly resistant mice susceptible
to L. major infection (90, 91). In addition, administration of
anti-IL-4 antibody to BALB/c mice renders them resistant
to L. major infection (92). Conversely, IL-4 blockade or
IL-12 administration renders resistant mice susceptible to the helminth infections Trichuris muris, Heligmosomoides polygyrus, and N. brasiliensis infections (29, 93, 94).
In these models, a Th0 response, characterized by a mixture of Th1 and Th2 cytokines, is often seen initially.
However, the immune response in these models typically
commits along Th1 or Th2 lines by 1-2 wk after infectious
challenge (90, 92, 95). It is still not known whether the
dual Th1/Th2 phenotype in this antitumor response is produced by one or two different populations of Th cells.
However, because the RT-PCR cytokine data at the challenge site were obtained 18 d after vaccination, the mice most likely had already differentiated past the Th0 stage.
Furthermore, the finding that complete rejection of challenge tumors introduced 2 wk after vaccination requires
both IL-4 and -IFN-dependent responses suggests that
the dual Th1/Th2 response persists for an extended period
of time.
It also remains to be determined whether the dual Th1/ Th2 effector response seen here is a general characteristic of other cell-based tumor vaccines, or is unique to the mechanism by which paracrine GM-CSF production initiates immune responses. Interestingly, a similar Th1/Th2 pattern was seen in response to a defined tumor antigen, i.e., a B cell lymphoma idiotype protein after immunization with GM-CSF producing lymphoma cells (98). Further characterization of the Th response made by antigen-specific T cells in response to tumor vaccination is being performed currently using TCR transgenic mice specific for a defined tumor antigen. It is likely that one of the reasons for the superiority of paracrine GM-CSF vaccines relative to other cytokine-transduced vaccines relates to the central role of GM-CSF in inducing bone marrow progenitors to differentiate into dendritic cells. Currently, we are attempting to determine whether dendritic cells that differentiate under GM-CSF control are uniquely capable of inducing and maintaining Th1 and Th2 differentiation simultaneously.
These findings of induction and maintenance of simultaneous Th1 and Th2 responses are somewhat surprising,
given that Th1-associated cytokines such as IL-12 and
-IFN inhibit Th2 differentiation and Th2-associated cytokines such as IL-4 and IL-10 inhibit Th1 differentiation.
Currently, we do not know whether the dual Th1/Th2 response is based on the development of Th cells that simultaneously produce Th1 and Th2 cytokines, or a mixture of
separate Th1 and Th2 populations. Nonetheless, the finding that Th1 and Th2 effector mechanisms can actually collaborate with each other in directing an effective antitumor
response rather than antagonizing each other has important
implications for the development of cancer immunotherapies in general. Ultimately, the most effective cancer immunotherapies may indeed be those that can simultaneously marshal multiple Th1 and Th2 effector mechanisms
that can cooperate in most effectively killing both the primary cancer and metastatic tumor deposits.
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Footnotes |
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Address correspondence to Hyam Levitsky, Johns Hopkins University School of Medicine, 347 Ross Bldg., 720 Rutland Ave., Baltimore, MD 21205. Phone: 410-614-0552; Fax: 410-614-9705; E-mail: hy{at}welchlink.welch.jhu.edu
Received for publication 25 September 1998 and in revised form 19 October 1998.
1 Abbreviations used in this paper: iNOS, inducible nitric oxide synthase; NO, nitric oxide.We would like to thank Dr. Tak Mak for providing the CD4/
and CD8
/
mice, Dr. Eric Pearlman for
the IL-5
/
mice, and Dr. Mary Dinauer for the X-CGD mice.
This work was supported by Public Health Service grant AI/AG37934-01 and gifts from the Topercer family. H. Levitsky is a Scholar of the Leukemia Society of America.
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