|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 778-783
Involvement of Interleukin-3 in Delayed-Type Hypersensitivity
By
Nicolas Mach,
Chris S. Lantz,
Stephen J. Galli,
Glen Reznikoff,
Martin Mihm,
Clayton Small,
Richard Granstein,
Stefan Beissert,
Michel Sadelain,
Richard C. Mulligan, and
Glenn Dranoff
From the Departments of Medicine, Dana-Farber Cancer Institute and
Harvard Medical School; the Departments of Pathology, Beth Israel
Deaconess Medical and Harvard Medical School; the Departments of
Pathology, Massachusetts General Hospital and Harvard Medical School;
Howard Hughes Medical Institute, Children's Hospital, and the
Department of Genetics, Harvard Medical School, Boston, MA; the
Department of Dermatology, Cornell University Medical College, New
York, NY; the Department of Dermatology, University of Munster,
Munster, Germany; and the Department of Human Genetics and Immunology
Program, Memorial Sloan-Kettering Cancer Center, New York, NY.
 |
ABSTRACT |
The in vivo functions of interleukin-3 (IL-3) were investigated by
generating IL-3-deficient mice. Although hematopoiesis was unimpaired
in homozygous mutant animals, contact hypersensitivity reactions were
compromised. IL-3 was required for efficient priming of hapten-specific
contact hypersensitivity responses, but was dispensable for
T-cell-dependent sensitization to tumor cells. These findings reveal a
critical role for IL-3 in some forms of delayed-type hypersensitivity.
| |
INTRODUCTION |
INTERLEUKIN-3 (IL-3) is a 28-kD
glycoprotein initially identified by its ability to induce the
expression of 20 -hydroxysteroid dehydrogenase in cultures of nude
mouse spleen cells.1 Subsequent work showed that the
cytokine can promote the in vitro differentiation and proliferation of
hematopoietic progenitors, yielding multipotential blast cells, mast
cells, basophils, neutrophils, macrophages, eosinophils, erythrocytes,
megakaryocytes, and dendritic cells.2-4 Administration of
IL-3 to mice, monkeys, and humans can stimulate hematopoiesis in vivo
as well.5-8 IL-3 can also enhance antigen presentation for
T-cell-dependent responses, augment macrophage cytotoxicity and
adhesion, and promote the function of eosinophils, basophils, and mast
cells.9-13
Despite these numerous activities, the functions of IL-3 in vivo remain
unclear. Mice carrying an inactivating mutation in the -chain of the
heterodimeric IL-3 receptor are apparently normal, and hematopoiesis
can occur in vitro in the absence of IL-3.14,15 While T
lymphocytes and mast cells can produce IL-3 in culture, the sources and
circumstances in which IL-3 is expressed in vivo are not fully
defined.16,17 To elucidate further the in vivo roles of
this molecule, we generated mice lacking IL-3 by homologous
recombination in embryonic stem (ES) cells.
| |
MATERIALS AND METHODS |
Generation of IL-3-deficient mice.
A 9.1-kb Xba I fragment and 3.1-kb BamHI-EcoRI
fragment spanning the murine IL-3 locus were isolated from a 129S ES
cell genomic library and inserted into the targeting vector
pPNT.18 The HindIII site in exon 1 was destroyed
during the construction. This vector was electroporated into D3 ES
cells19 and clones resistant to G418 and ganciclovir were
analyzed by Southern analysis as previously described.18
The 600-bp probe indicated in Fig 1 was
used to identify the 6.5-kb wild type and 9.5-kb targeted fragments
after HindIII digestion. Targeted clones were injected into
C57BL/6 blastocysts as described to generate chimeric animals
transmitting the mutant allele through the germ line.20
Heterozygous mice were mated to generate mice homozygous for the
targeted mutation. For genotyping of animals, tail DNA was digested
with HindIII and probed as above. The IL-3 mutation was
backcrossed four generations onto both the BALB/c and C57BL/6 strains.
View larger version (15K):
[in this window]
[in a new window]
View larger version (55K):
[in this window]
[in a new window]
| Fig 1.
Generation of IL-3-deficient mice. (A) Structure of IL-3
targeting vector and disrupted IL-3 gene. The 600-bp probe indicated identifies the 6.5-kb wild-type and 9.5-kb targeted fragments after
HindIII digestion as shown. X, Xba I; H,
HindIII; B, BamHI; R, EcoRT. (B) Genotype of
mutant animals. Tail DNA was digested with HindIII and probed
as above. Molecular sizes are indicated on the left (in kilobases).
|
|
Hematologic evaluation.
Peripheral blood was analyzed for hematocrit, total and differential
white blood cell counts, and platelet counts, and bone marrow cells and
splenocytes were assayed for CFU-G, CFU-M, CFU-GM, and CFU-GEMM as
previously described.21 For bone marrow transplantation experiments, 5 × 106 nucleated blood cells harvested from
donor femurs were injected into lethally irradiated recipients (1,100 rads in two doses). Peripheral blood counts were determined at days 9, 23, 64, and 100 posttransplantation.
Contact hypersensitivity.
Mice at least 6 weeks of age were sensitized on day 0 with 50 µL of
4% 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone; Sigma, St
Louis, MO) in acetone/olive oil (4/1) painted onto the shaved abdomen
and were challenged on day 5 with 20 µL of 0.5% oxazolone or carrier
only painted on the left and right ear, respectively. To assess
responsiveness to 2,4-dinitrofluorobenzene (DNFB; Sigma), mice were
sensitized on days 0 and 1 with 20 µL of 0.5% DNFB in acetone/olive
oil (4/1) and then challenged on day 5 with 20 µL with 0.2% DNFB. To
assess responsiveness to fluorescein isothiocyanate (FITC; Sigma), mice
were sensitized on day 0 with 400 µL of 0.5% FITC in acetone/dibutyl
pthalate (1/1) and challenged on day 6 with 20 µL of 0.5% FITC. The
hapten-specific increase in ear thickness at 24 hours was determined
with a micrometer. For analysis of fibrin deposition,
125I-labeled guinea pig fibrinogen was injected
intravenously 10 minutes before secondary oxazolone challenge in
sensitized mice. Twenty-four hours later ears were removed and the urea
insoluble extract (cross-linked fibrin) assayed for 125I as
previously described.22
Tumor vaccinations.
Female mice (on the BALB/c background) were immunized subcutaneously on
the abdomen with 5 × 105 irradiated (3,300 rads) RENCA
carcinoma cells (cultured in DME plus 10% fetal calf
serum and antibiotics) and challenged 7 days later with 1 × 107 live RENCA cells subcutaneously on the back. Mice were
killed when challenge tumors reached 2 cm in diameter. RENCA cells do not secrete detectable IL-3 as measured by enzyme-linked immunosorbent assay (ELISA) with a sensitivity of 25 pg/mL. For evaluation of delayed-type hypersensitivity to tumor cells, female BALB/c mice were
immunized subcutaneously on the abdomen with 5 × 105
irradiated RENCA carcinoma cells and 7 days later were injected in the
footpads with 5 × 106 irradiated RENCA cells.
Tumor-induced footpad swelling at 24 hours was determined with a
micrometer. For haptenized tumor cell experiments, irradiated RENCA
cells were incubated for 15 minutes at 37°C in 70 mmol/L
oxazolone (dissolved in Hanks' balanced salt solution [HBSS] and
ethanol, pH 7). The cells were then extensively washed with HBSS and
injected subcutaneously for sensitization.
Cytokine mRNA expression.
Total RNA was obtained with TRIZOL (GIBCO-BRL, Grand Island,
NY) according to the manufacturer's instructions. cDNA
was synthesized using oligo-dT primers and MMLV reverse transcriptase
(GIBCO-BRL). Polymerase chain reaction (PCR) was performed using
published IL-3 primers.23 Amplified bands were confirmed as
IL-3 by Southern blotting using IL-3 cDNA as a probe.
| |
RESULTS AND DISCUSSION |
Development of mice lacking IL-3.
To generate a null allele of the IL-3 gene, a neomycin-resistance
cassette was introduced by homologous recombination into the third exon
of the IL-3 locus (Fig 1A). Targeted clones were injected into C57BL/6
blastocysts to yield chimeric animals, which were then mated with
C57BL/6 mice to obtain germline transmission of the mutant allele.
Heterozygous mutant animals were interbred to generate homozygous
IL-3-deficient animals (Fig 1B). Mutant mice were obtained at the
expected frequencies, remained clinically healthy throughout 18 months
of observation, and were fertile. Supernatants of concanavalin
A-stimulated splenocytes from mutant animals showed no immunoreactive
or bioactive IL-3, as determined by both proliferative studies with the
32D myeloid cell line24 and ELISA (not shown).
Complete pathologic examination of IL-3-deficient animals showed no
abnormalities. Analysis of steady-state hematopoiesis demonstrated
normal numbers of peripheral blood cells, bone marrow and splenic
hematopoietic progenitors (as measured by colony-forming unit assays),
and tissue hematopoietic populations. Bone marrow obtained from
IL-3-deficient mice reconstituted lethally irradiated IL-3-deficient
recipients with comparable kinetics as wild-type marrow transplanted
into wild-type recipients. These results, which are consistent with
recently reported findings,25 show that IL-3 is dispensable
for normal hematopoiesis in vivo.
Impaired contact hypersensitivity reactions in IL-3-deficient mice.
To evaluate the potential role of IL-3 in T-cell-dependent immunity,
wild-type and mutant animals were tested for the development of contact
hypersensitivity to epicutaneously applied oxazolone. Contact
hypersensitivity is a form of delayed-type hypersensitivity in which
hapten-protein conjugates formed in the skin are presented by epidermal
Langerhans cells, following their migration to regional lymph nodes, to
hapten-specific CD4+ and CD8+ T
lymphocytes.26-28 Sensitized T cells initiate a local
inflammatory response in the skin upon secondary hapten challenge.
Although IL-3-deficient mice were indistinguishable from wild-type
littermates in the magnitude of their immunologically nonspecific
"irritant" response to initial hapten challenge (data not shown),
they exhibited significantly compromised reactivity upon secondary
hapten challenge, as measured by ear swelling (Fig
2A). Impairment was evident in nine
experiments with IL-3-deficient mice in the C57BL/6 background and
seven experiments in the BALB/c background, and was also observed in
four other experiments in which 2,4-dinitrofluorobenzene or fluorescein
isothiocyanate were used as haptens.
View larger version (26K):
[in this window]
[in a new window]
View larger version (16K):
[in this window]
[in a new window]
View larger version (15K):
[in this window]
[in a new window]
View larger version (30K):
[in this window]
[in a new window]
| Fig 2.
Delayed-type hypersensitivity reactions. (A) Contact
hypersensitivity reactions to oxazolone in IL-3-deficient ( ) and
wild-type littermates ( ). Values (n = 5) are mean ± SEM:
C57BL/6, P = .025; BALB/c, P = .014. (B) Fibrin
deposition during contact hypersensitivity to oxazolone (C57BL/6
background). P < .001 for oxazolone challenge. Plasma values
for 125I-labeled fibrinogen 24 hours after injection
were 1,948 ± 61.7 for +/+ mice and 1,879 ± 53.3 cpm for
 / animals. (C) Tumor protection in immunized female
IL-3-deficient ( ) and wild-type littermates ( ) (BALB/c
background). Wild-type controls, no vaccine (). All surviving
animals at day 55 were tumor free. Pooled results from two independent
experiments (10 mice per group). (D) Delayed-type hypersensitivity to
irradiated tumor cells inoculated in the footpads of immunized female
IL-3-deficient () and wild-type littermate mice () (BALB/c
background).
|
|
To examine the defective contact hypersensitivity reaction in more
detail, 125I-fibrinogen was injected systemically into
IL-3-deficient and wild-type control mice at the time of secondary
oxazolone challenge.22 The conversion of fibrinogen to
cross-linked fibrin at the challenge site results in the induration
characteristic of cutaneous delayed-type hypersensitivity responses.
Significantly less cross-linked fibrin was present in the ears of
IL-3-deficient mice as compared with wild-type littermates (Fig 2B),
confirming a marked reduction in the magnitude of the hapten-specific
immune response.
Although no histolopathologic differences between IL-3-deficient and
wild-type mice were noted in untreated skin or in skin at the
sensitization site, marked differences were apparent in the challenge
site (Fig 3B and C). In wild-type animals,
the inflammatory response was characterized by an intense cellular
infiltrate consisting predominantly of neutrophils, lymphocytes, and
eosinophils, as well as substantial dermal edema, hyperkeratosis, and
focal intraepidermal abscesses. IL-3-deficient animals, in contrast,
developed a dramatically less intense cellular infiltrate, although the
cellular composition was similar to that of wild-type animals.
IL-3-deficient mice also demonstrated less edema, fewer and smaller
intraepidermal abscesses, and little keratinocyte activation. The
number of Langerhans cells in the skin of unmanipulated IL-3-deficient
mice, as determined by immunofluorescence staining of major
histocompatibility complex class II positive cells in epidermal ear
sheets, however, was comparable to that of wild-type littermate
controls (1,663 ± 362 v 1,433 ± 271/mm2 of
epidermal surface for IL-3-deficient and wild-type animals).
View larger version (30K):
[in this window]
[in a new window]
View larger version (85K):
[in this window]
[in a new window]
View larger version (107K):
[in this window]
[in a new window]
View larger version (123K):
[in this window]
[in a new window]
| Fig 3.
IL-3 is required for hapten specific priming. (A)
IL-3-deficient () and wild-type littermate controls () (BALB/c)
were tested for contact hypersensitivity to oxazolone. One hundred
nanograms of murine IL-3 (in 1% mouse serum) () or vehicle only was
administered intraperitoneally and subcutaneously (abdomen) 4 hours
before, at the time of sensitization, and 6 hours afterwards. +/+
versus /, P = .03. / plus murine IL-3 versus
/, P = .008. Murine IL-3 administered to unsensitized
mice had no effect on secondary challenge. (B through D) Histopathology
(tissues were formalin-fixed, paraffin-embedded, and stained with
hematoxylin and eosin) of secondary oxazolone challenge sites in ears
from mice (BALB/c background) killed 24 hours after challenge. (B) Ear
reaction of a sensitized wild-type mouse. (C) Ear reaction of a
sensitized IL-3-deficient mouse. (D) Ear reaction of a sensitized
IL-3-deficient mouse administered IL-3 protein at the time of priming.
|
|
Tumor vaccination responses in IL-3-deficient mice.
To address the potential involvement of IL-3 in another type of
cutaneous delayed-type hypersensitivity reaction, we evaluated the
ability of IL-3-deficient mice to generate antitumor immunity after
vaccination with irradiated tumor cells. Tumor immunization in this
system, like contact hypersensitivity,28 is dependent on
CD4+ and CD8+ T cells (J. Donahue
and G. Dranoff, manuscript in preparation). Nonetheless,
IL-3-deficient mice showed no impairment in tumor vaccination, as
measured by the ability to reject a secondary challenge of live tumor
cells, under conditions where immunized wild-type mice demonstrated
only partial protection against tumor challenge (Fig 2C). Moreover,
tumorigenicity in naive IL-3-deficient mice was indistinguishable from
wild-type littermates. Pathologic examination of tumor rejection sites
in immunized animals showed no significant differences between
IL-3-deficient and wild-type mice. The generation of antitumor
immunity was also assessed by injecting irradiated tumor cells into the
footpads of previously vaccinated animals. No differences were observed
between IL-3-deficient and wild-type mice, as measured by
tumor-induced footpad swelling (Fig 2D).
IL-3 expression during delayed-type hypersensitivity.
To investigate the potential basis for the differing requirements for
IL-3 in the two forms of delayed-type hypersensitivity, the expression
of IL-3 in the skin during the priming phases of the two responses was
examined by reverse transcriptase (RT)-PCR (Table
1). Although IL-3 transcripts were not
detected in unmanipulated or shaved skin, or in skin treated only with
diluent, the application of hapten rapidly induced IL-3 transcripts in
wild-type, but not IL-3-deficient, animals. Expression was detected as
early as 1 hour after hapten painting and persisted for up to 4 days.
IL-3 transcripts were also found in the draining lymph node of the sensitization site 24 hours after hapten application. In contrast to
these findings, IL-3 transcripts were not detected in the skin of
wild-type mice after vaccination with irradiated tumor cells.
To evaluate the potential role of IL-3 during the priming phase of
contact hypersensitivity, IL-3 protein was administered subcutaneously
and intraperitoneally at the time of sensitization to IL-3-deficient
animals. This resulted in partial correction of the impaired response,
as measured by ear swelling (Fig 3A). Moreover, pathologic analysis
showed a significant increase in the intensity of the inflammatory
response in comparison to untreated mutant animals, but the reaction
did not reach wild-type levels (Fig 3D). The inability to correct
completely the defective response in IL-3-deficient mice could be due
to either pharmacologic limitations in the delivery of IL-3 protein or
a second role for IL-3 during the elicitation phase. Indeed, IL-3
transcripts were also detected in the skin upon secondary hapten
challenge, and previous work has shown that administering neutralizing
antibodies to both IL-3 and granulocyte-macrophage colony-stimulating
factor during the elicitation phase can reduce the intensity of the
reaction.29 However, attempts to correct the impaired
response in IL-3-deficient mice by providing IL-3 at the time of
elicitation were unsuccessful.
The requirement for IL-3 during delayed-type hypersensitivity to
haptens, but not tumor cells, demonstrates that distinct pathways
underlie the generation of T-cell immunity in the skin. In this
context, sensitization with haptenated tumor cells was also compromised
in IL-3-deficient mice (data not shown), suggesting that intact
priming to tumor cells could not overcome the IL-3-associated impairment in hapten-specific responses. Further studies will be
necessary to delineate whether different antigen presenting cells or
functions are involved in the responses to haptens and tumor cells, and
whether other techniques of hapten administration can bypass the defect
shown here or whether other techniques of tumor vaccination are
dependent on IL-3. The sources of IL-3 production in normal skin remain
to be clarified as well, although Langerhans cells, mast cells, and
keratinocytes are possibilities. Finally, our results suggest that IL-3
antagonists might be effective therapies for contact dermatitis in
humans.
| |
FOOTNOTES |
Submitted September 18, 1997;
accepted November 14, 1997.
Supported by the Claudia Adams Barr Foundation, a Young Markey
Scientist Award, the Cancer Research Institute/Partridge Foundation (G.D.), the Swiss National Science Foundation (N.M.), CA72074 and
AI23990 (S.J.G.), and AR40667 (R.G.).
Address reprint requests to Glenn Dranoff, MD, Dana-Farber Cancer
Institute, Dana 710E, 44 Binney St, Boston, MA 02115.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
All mouse experiments were approved by the
AAALAC-accredited DFCI IACUC. We thank C. Crawford, A. Crawford, B. Ream, K. Edelman, R. Bronson, and V. Tybulewicz for their
excellent help. We thank the staff of the Redstone Animal Facility for
their excellent maintenance of the mouse colony.
| |
REFERENCES |
1.
Ihle JN,
Weinstein Y:
Immunological regulation of hematopoietic/lymphoid stem cell differentiation by interleukin 3.
Adv Immunol
39:1,
1986[Medline]
[Order article via Infotrieve]
2.
Rennick DM,
Lee FD,
Yokota T,
Arai KI,
Cantor H,
Nabel GJ:
A cloned MCGF cDNA encodes a multilineage hematopoietic growth factor: Multiple activities of interleukin 3.
J Immunol
134:910,
1985[Abstract]
3.
Suda T,
Suda J,
Ogawa M,
Ihle JN:
Permissive role of interleukin-3 in proliferation and differentiation of multipotential hemopoietic progenitors in culture.
J Cell Physiol
1124:182,
1985
4.
Caux C,
Vanbervliet B,
Massacrier C,
Durand I,
Banchereau J:
Interleukin-3 cooperates with tumor necrosis factor-alpha for the development of human dendritic Langerhans cells from cord blood CD34(+) hematopoietic progenitor cells.
Blood
87:2376,
1996[Abstract/Free Full Text]
5.
Metcalf D,
Begley CG,
Johnson GR,
Nicola NA,
Lopez AF,
Williamson DJ:
Effects of purified bacterially synthesized murine multi-CSF (IL-3) on hematopoiesis in normal adult mice.
Blood
68:46,
1986[Abstract/Free Full Text]
6.
Kindler V,
Thorens B,
de Kossodo S,
Allet B,
Eliason JF,
Thatcher D,
Farber N,
Vassalli P:
Stimulation of hematopoiesis in vivo by recombinant bacterial murine interleukin 3.
Proc Natl Acad Sci USA
83:1001,
1986[Abstract/Free Full Text]
7.
Donahue RE,
Seehra J,
Metzger M,
Lefebvre D,
Rock B,
Carbone S,
Nathan DG,
Garnick M,
Sehgal PK,
Laston D,
LaVallie E,
McCoy J,
Schendel PF,
Norton C,
Turner K,
Yang Y-C,
Clark SC:
Human IL-3 and GM-CSF act synergistically in stimulating hematopoiesis in primates.
Science
241:1820,
1988[Abstract/Free Full Text]
8.
Gianella-Borradori A:
Present and future clinical relevance of interleukin 3.
Stem Cells
12:241,
1994[Abstract]
9.
Rothenberg M,
Owen W,
Silberstein D,
Woods J,
Soberman R,
Austen K,
Stevens R:
Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin-3.
J Clin Invest
81:1986,
1988
10.
Kimoto M,
Kindler V,
Higaki M,
Ody C,
Izui S,
Vassalli P:
Recombinant murine IL-3 fails to stimulate T or B lymphopoiesis in vivo, but enhances immune responses to T cell-dependent antigens.
J Immunol
140:1889,
1988[Abstract/Free Full Text]
11.
Cannistra SA,
Vellenga E,
Groshek P,
Rambaldi A,
Griffin JD:
Human granulocyte-macrophage colony-stimulating factor and interleukin-3 stimulate monocyte cytotoxicity through a tumor necrosis factor-dependent mechanism.
Blood
71:672,
1988[Abstract/Free Full Text]
12. Madden KB, Urban JF, Jr., Ziltener HJ, Schrader JW, Finkelman
FD, Katona IM: Antibodies to IL-3 and IL-4 suppress helminth-induced
intestinal mastocytosis. J Immunol 147:1387, 1991
13.
Pulaski BA,
Yeh KY,
Shastri N,
Maltby KM,
Penney DP,
Lord EM,
Frelinger JG:
Interleukin 3 enhances cytotoxic T lymphocyte development and class I major histocompatibility complex re-presentation of exogenous antigen by tumor-infiltrating antigen-presenting cells.
Proc Natl Acad Sci USA
93:3669,
1996[Abstract/Free Full Text]
14.
Li CL,
Johnson GR:
Stimulation of multipotential, erythroid and other murine haematopoietic progenitor cells by adherent cell lines in the absence of detectable multi-CSF (IL-3).
Nature
316:633,
1985[Medline]
[Order article via Infotrieve]
15.
Ichihara M,
Hara T,
Takagi M,
Cho LC,
Gorman DM,
Miyajima A:
Impaired interleukin-3 (IL-3) response of the A/J mouse is caused by a branch point deletion in the IL-3 receptor alpha subunit gene.
EMBO J
14:939,
1995[Medline]
[Order article via Infotrieve]
16.
Plaut M,
Pierce JH,
Watson CJ,
Hanley-Hyde J,
Nordan RP,
Paul WE:
Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores.
Nature
339:64,
1989[Medline]
[Order article via Infotrieve]
17. Svetic A, Madden K, di Zhou X, Lu P, Katona I, FD F, Urban J,
Gause W: A primary intestinal helminthic infection rapidly induces a
gut-associated elevation of Th2-associated cytokines and IL-3. J
Immunol 150:3434, 1993
18.
Tybulewicz V,
Crawford C,
Jackson P,
Bronson R,
Mulligan RC:
Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene.
Cell
65:1153,
1991[Medline]
[Order article via Infotrieve]
19.
Doetschman T,
Eistetter H,
Katz M,
Schmidt W,
Kemler R:
The in vitro development of blastocyst-derived embryonic stem cell lines: Formation of visceral yolk sac, blood islands and myocardium.
J Embryol Exp Morph
87:27,
1985[Medline]
[Order article via Infotrieve]
20. Bradley A: Production and analysis of chimeric mice, in
Robertson EJ (ed): Teratocarcinomas and Embryonic Stem Cells: A
Practical Approach. Oxford, UK, IRL, 1987, p 113
21. (suppl 1)
Dranoff G,
Mulligan RC:
Activities of granulocyte-macrophage colony stimulating factor revealed by gene transfer and gene knockout studies.
Stem Cells
12:173,
1994
22.
Mekori YA,
Dvorak HF,
Galli SJ:
125I-fibrin deposition in contact sensitivity reactions in the mouse. Sensitivity of the assay for quantitating reactions after active or passive sensitization.
J Immunol
136:2018,
1986[Abstract]
23.
Montgomery RA,
Dallman MJ:
Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction.
J Immunol
147:554,
1991[Abstract]
24. Hapel A, HS W, DA H: Different colony stimulating factors are
detected by the "interleukin-3" dependent cell lines FDC-P1 and
32D c1-23. Blood 64:786, 1984
25.
Nishinakamura R,
Miyajima A,
Mee P,
Tybulewicz V,
Murray R:
Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions.
Blood
88:2458,
1996[Abstract/Free Full Text]
26.
Eisen HN,
Orris L,
Belman S:
Elicitation of delayed allergic skin reactions with haptens: The dependence of elicitation on hapten combination with protein.
J Exp Med
95:473,
1952[Abstract]
27.
Silberberg I,
Baer RL,
Rosenthal SA:
The role of Langerhans cells in allergic contact hypersensitivity. A review of findings in man and guinea pigs.
J Invest Derm
66:210,
1976[Medline]
[Order article via Infotrieve]
28.
Gocinski BL,
Tigelaar RE:
Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion.
J Immunol
144:4121,
1990[Abstract]
29.
Piguet PF,
Grau GE,
Hauser C,
Vassalli P:
Tumor necrosis factor is a critical mediator in hapten induced irritant and contact hypersensitivity reactions.
J Exp Med
173:673,
1991[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
T. Shen, S. Kim, J.-s. Do, L. Wang, C. Lantz, J. F. Urban, G. Le Gros, and B. Min
T cell-derived IL-3 plays key role in parasite infection-induced basophil production but is dispensable for in vivo basophil survival
Int. Immunol.,
July 15, 2008;
(2008)
dxn077v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Enzler, S. Gillessen, M. Dougan, J. P. Allison, D. Neuberg, D. A. Oble, M. Mihm, and G. Dranoff
Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of {beta} cells
Blood,
August 1, 2007;
110(3):
954 - 961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jiang, E. Ng, C. Yip, W. Eisterer, Y. Chalandon, M. Stuible, A. Eaves, and C. J. Eaves
Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo
Blood,
November 15, 2002;
100(10):
3731 - 3740.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. G. Jegalian, A. Acurio, G. Dranoff, and H. Wu
Erythropoietin receptor haploinsufficiency and in vivo interplay with granulocyte-macrophage colony-stimulating factor and interleukin 3
Blood,
April 1, 2002;
99(7):
2603 - 2605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Wang, C. Feliciani, I. Freed, Q. Cai, and D. N. Sauder
Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies
J. Leukoc. Biol.,
August 1, 2001;
70(2):
185 - 191.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Li, S. Gillessen, M. H. Tomasson, G. Dranoff, D. G. Gilliland, and R. A. Van Etten
Interleukin 3 and granulocyte-macrophage colony-stimulating factor are not required for induction of chronic myeloid leukemia-like myeloproliferative disease in mice by BCR/ABL
Blood,
March 1, 2001;
97(5):
1442 - 1450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Gillessen, N. Mach, C. Small, M. Mihm, and G. Dranoff
Overlapping roles for granulocyte-macrophage colony-stimulating factor and interleukin-3 in eosinophil homeostasis and contact hypersensitivity
Blood,
February 15, 2001;
97(4):
922 - 928.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Gainsford, H. Nandurkar, D. Metcalf, L. Robb, C. G. Begley, and W. S. Alexander
The residual megakaryocyte and platelet production in c-Mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor
Blood,
January 15, 2000;
95(2):
528 - 534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Abstract
Introduction
Abstract