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Cutting Edge |
Cellular Immunology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism by which CD4+CD25+ T cells prevent the development of autoimmune disease remains unknown (3). One difficulty in the interpretation of many of the earlier studies is that most of the protocols, including d3Tx (4), involved induction of a generalized state of partial lymphocyte depletion or transfer of cells to a lymphopenic host in addition to depletion of CD4+CD25+ T cells. Indeed, it has been proposed that the lymphopenic state itself may promote the activation of autoreactive effector cells and that reconstitution of a depleted animal with either CD4+CD25+ or CD4+CD25- would prevent disease development (4, 5). A much more direct test of the role of CD4+CD25+ T cells in regulating the development of autoimmunity in vivo would be their selective removal from the intact animal. In the present report, we have attempted to define the requirements for induction of autoimmune disease following depletion of CD4+CD25+ T cells. We demonstrate that selective depletion of CD4+CD25+ only rarely results in the development of autoimmunity and that an additional signal is required to activate autoreactive effector CD4+CD25- T cells. This signal may be supplied by the induction of proliferation following transfer to a lymphopenic environment or by activation of the effector T cells via strong stimulation of their TCR with specific Ag.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c females (6–8 wk old), 14-day gestation BALB/c females, BALB/c nu/nu females (6–8 wk old), and C.B-17 SCID females (6–8 wk old) were purchased from the National Cancer Institute animal facility (Frederick, MD) and housed under specific pathogen-free conditions. H/K ATPase was obtained by purification of microsomes from rabbit stomach (6). PC61 (anti-CD25) hybridoma was purchased from American Type Culture Collection (Manassas, VA) and ascites was produced in C.B-17 SCID mice. For all injections, an ammonium sulfate cut of PC61 ascites was used. Abs purchased from BD PharMingen (San Diego, CA) were FITC-anti-CD25 (7D4) and PE-anti-CD25 (PC61). Tri-color (TC)-anti-CD4 was purchased from Caltag Laboratories (Burlingame, CA). Rat IgG was purchased from Jackson ImmunoResearch Laboratories (West Grove, PA). CFSE was purchased from Molecular Probes (Eugene, OR).
In vivo depletion, immunization with H/K ATPase, and assessment of AIG
BALB/c mice were given 1 mg PC61 every 3 days i.p. beginning day 10 of life for 2 wk. Alternatively, mice were given three injections from days 17 to 23 or one injection on day 23 of life only. Depletion of CD25+ cells was confirmed by flow cytometry of PBMC using anti-CD4-Tri-color and anti-CD25-FITC (clone 7D4). All flow cytometry was performed on a BD FACScan or FACSCalibur and analyzed using CellQuest software (BD Immunocytometry Systems, San Jose, CA). After depletion, animals were followed until 3 mo of age and were analyzed for the production of anti-parietal cell Abs and gastric pathology (6).
PC61 treated or nontreated BALB/c mice were immunized s.c. in the hind flank with 50 µg of H/K ATPase containing rabbit microsomes emulsified in CFA or IFA in a volume of 50 µl. These animals were then assayed 6–10 wk later for anti-parietal cell Abs and gastric pathology.
Purification of cells and transfer to recipient animals
Splenocytes (10–20 x 106) from depleted and nondepleted animals were harvested and transferred i.v. into 6- to 8-wk-old BALB/c wild-type and nu/nu females. These animals were analyzed for anti-parietal cell Abs and gastric pathology at 5–6 wk posttransfer.
CD4+CD25- and CD4+CD25+ T cells were purified and in vitro suppression assays were performed as described previously (7). For some experiments cells were labeled with CFSE at a final concentration of 1 µM in PBS for 8 min at room temperature. Labeled CD4+CD25- or CD4+CD25+ T cells (5 x 106) were injected i.v. alone, or labeled CD4+CD25- T cells were injected in combination with unlabeled CD4+CD25- or CD4+CD25+ T cells (5 x 106) into BALB/c nu/nu animals. Labeled CD4+CD25- cells were also injected into BALB/c hosts as nonproliferating controls. Cell division was measured by loss of CFSE on live-gated CD4+ cells at various time points posttransfer by flow cytometry using a BD FACSCalibur and analyzed using CellQuest software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The anti-CD25 mAb, PC61, is capable of depleting
CD25+ cells in vivo (8). We
initially injected 1 mg of PC61 every other day for 2 wk beginning on
day 10 of life. One day after the last injection (day 24 of life),
CD25+ T cells were markedly depleted from
peripheral blood (Fig. 1
A,
10.5 to 0.8%). Identical results were observed when mice were injected
once on day 23 of life or every other day between days 17 and 23 (data
not shown). The depleted mice were followed until they were 3 mo of
age. A low (10%) but consistent incidence of spontaneous autoimmune
gastritis (AIG) was observed as measured by the presence of
autoantibodies to gastric parietal cells or gastric pathology (Fig. 1B). In contrast, when BALB/c mice are subjected to d3Tx,
the incidence of AIG is 
60%. To rule out the possibility that
depletion was not complete and that the low number of surviving
CD4+CD25+ cells were
capable of controlling the induction of autoimmunity, we transferred
splenocytes from 24-day-old PC61-depleted animals to BALB/c
nu/nu recipients. All (100%) of the PC61-depleted
splenocyte recipients developed severe destructive gastritis (Fig. 1C). As a positive control for suppression of the
development of disease in recipients, we cotransferred
CD4+CD25+ T cells from
normal adult mice with these splenocytes into nu/nu
recipients; none of the recipients of the cotransferred cells developed
AIG (data not shown).
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As we did not thymectomize the animals following depletion of the
CD25+ T cells, it remained possible that
CD25+ cells could be re-emerging from the thymus
and repopulating the periphery, controlling the induction of
autoimmunity. Indeed, analysis of the percentage of
CD4+CD25+ population at
different time points following depletion did reveal a slow, partial
recovery of the percentage of CD25+ T cells in
splenocytes, as well as peripheral blood with 3–4% of the CD4 pool
expressing CD25 at 6 wk postdepletion (Fig. 2A). To determine whether this
low number of CD25+ cells is capable of
suppressing the induction of AIG, we transferred splenocytes from
24-day-old depleted animals to nu/nu recipients at
various time points following depletion and monitored them for the
presence of AIG. Surprisingly, all nu/nu recipients had
severe destructive AIG (Fig. 2A), even when the transferred
CD4+ population contained as many as 4%
CD25+ T cells. To further substantiate that the
CD25+ T cells, which repopulated the depleted
animals, belonged to the naturally occurring
CD4+CD25+ pool and had not
acquired the expression of CD25 due to activation in vivo, we purified
CD25+ T cells from animals 6 wk after depletion
and evaluated their capacity to suppress the proliferative response of
CD25- T cells in vitro. The recovered
CD25+ T cells were as suppressive as
CD25+ T cells from normal mice (Fig. 2B).
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Many groups have demonstrated that CD4+ T
cells will rapidly divide nonspecifically in a lymphopenic environment
to restore T cell homeostasis (9, 10, 11, 12). As shown in Fig. 3A, CFSE-labeled
CD4+CD25- and
CD4+CD25+ T cells
proliferated comparably in the BALB/c nu/nu recipients; both
populations showed at least two divisions by day 7 and continued to
divide 21 days posttransfer. It has been proposed that one mechanism by
which CD4+CD25+ T cells can
control the induction of autoimmunity is to control the nonspecific
proliferation that takes place in a lymphopenic environment. If this
were the case then cotransfer of CD25- and
CD25+ T cells should resemble the proliferation
seen upon transfer into a wild-type BALB/c recipient (Fig. 3B, upper left). To evaluate the ability of
CD4+CD25+ T cells to
control lymphopenia-induced proliferation, we transferred CFSE-labeled
CD4+CD25- T cells alone or
with unlabeled CD4+CD25-
or CD4+CD25+ T cells to
wild-type or nu/nu recipients. Analysis of CFSE-labeled
CD4+CD25- T cells in the
presence of either unlabeled
CD4+CD25- (Fig. 3B, lower left) or
CD4+CD25+ (Fig. 3B, lower right) T cells revealed a similar
proliferation profile seen upon labeled
CD4+CD25- T cells
transferred alone (Fig. 3B, upper right) into a
BALB/c nu/nu host. Similar results were observed when the
CD4+CD25+ T cells were
injected 2 wk before injection of CFSE-labeled
CD4+CD25- T cells (data
not shown). As a control, some recipient animals were monitored for
development of AIG. All BALB/c nu/nu animals receiving
CD4+CD25- T cells alone
developed AIG, whereas all recipients of cotransferred
CD4+CD25+ T cells were free
of gastric pathology (data not shown).
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Immunization of BALB/c animals with the AIG target Ag H/K ATPase
in CFA has failed to induce sustained severe AIG in mice, although mice
can develop anti-parietal cell Abs. Gastric pathology is evident
while immunizations are ongoing but resolves once immunization is
ceased (13). We investigated whether immunization of
animals that were depleted of CD25+ cells would
result in severe AIG. Animals were either depleted of
CD25+ cells or left untreated and immunized the
following day with H/K ATPase in IFA. Mice immunized with H/K ATPase in
IFA were positive for anti-parietal cell Abs, but only animals that
were depleted of CD25+ cells and immunized with
Ag and IFA had severe gastric pathology 5 wk postimmunization (Fig. 4). As a control, untreated mice
immunized with H/K ATPase in CFA failed to show signs of gastric
pathology. Induction of nonspecific inflammation by injection of IFA
alone did not result in the induction of AIG (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In an attempt to more accurately define a role for CD4+CD25+ suppressor T cells in the control of organ-specific autoimmune disease in the absence of lymphopenia-induced proliferation, we selectively depleted them with Ab. Depleted animals only rarely developed AIG, the most common manifestation of a deficiency of regulatory T cell function in BALB/c mice. This result must be compared with that of Taguchi and Takahashi (8), who observed a significant increase in organ-specific autoimmune disease using a very similar protocol. This difference may be secondary to the different animal strains used, as our studies involved the induction of AIG in BALB/c mice, whereas Taguchi and Takahashi (8) used (B6 x A/J)F1 animals, which are more susceptible to diseases of the reproductive system following d3Tx. Curiously, CD25-depleted (B6 x A/J)F1 mice developed gastritis, normally not observed in that strain after d3Tx, while they failed to develop diseases of the reproductive system. Importantly, our data are consistent with studies (14, 15) in which depletion of CD25+ cells to induce tumor immunity did not enhance susceptibility to autoimmune disease. One trivial explanation for our failure to observe autoimmune disease following depletion of CD25+ T cells in euthymic animals is that the depletion was inadequate or that new thymic emigrants rapidly repopulated the CD4+CD25+ pool. This explanation is highly unlikely, because transfer of T cells from CD25-depleted animals to nu/nu recipients for up to 6 wk following depletion resulted in the induction of autoimmune disease in 100% of recipients, even when partial reconstitution of the CD25+ population was observed.
The disparity between the ability to transfer disease to a lymphopenic animal, while the lymphocyte-sufficient, CD25-depleted donor does not develop autoimmune disease, forced us to reexamine the contribution of lymphopenia for the induction of organ-specific autoimmunity. Annacker et al. (16) have proposed that a primary function of CD4+CD25+ T cells is to regulate the homeostatic proliferation of peripheral T cells, most likely by the secretion of IL-10. However, the concept of homeostatic proliferation must be clearly defined. In the lymphopenic animal, transferred T cells are stimulated through TCR/MHC interactions to proliferate and fill the "empty" space to reach T cell homeostasis (17). Unseparated CD4+, CD4+CD25- (CD45RBhigh), and CD4+CD25+ T cells are capable of proliferating in a lymphopenic host with proliferation beginning on days 3–4 posttransfer and reaching as many as eight divisions by days 21–28 (12, 16). We did not observe a suppressive effect of cotransfer of CD4+CD25+ T cells on this early phase of proliferation of CD4+CD25- T cells, particularly when compared with cotransfer of an equivalent number of CD4+CD25- T cells. It is likely that the modest reduction of the proliferation of CD4+CD25- T cells observed by Annacker et al. (16) by cotransfer of CD4+CD25+ T cells was secondary to an overall increase in the number of injected T cells (12). Cotransfer of CD4+CD25- T cells was not examined by Annacker et al. (16).
In contrast to the lack of an effect of CD4+CD25+ T cells on the early phase of the expansion of CD4+CD25- T cells, regulatory T cells have been reported to exert a profound effect on the accumulation or steady state numbers of CD4+CD25- T cells when the recipient animals are studied 2–6 mo after cell transfer (16, 18). This suppressive effect of cotransfer of CD4+CD25+ T cells on the late accumulation of CD4+CD25- T cells must be interpreted with caution. Recipients of CD4+CD25- T cells frequently develop autoimmune diseases (1, 19) and therefore have undergone Ag-specific stimulation and expansion in addition to lymphopenia-driven T cell proliferation. CD4+CD25+ T cells are known to inhibit the induction of these autoimmune diseases. Indeed, the requirement for IL-10 to control the late expansion of the CD4+CD25- in BALB/c recombination-activating gene 2-/- mice reported by Annacker et al. (16) is most consistent with the requirement for IL-10 production by CD4+CD25+ T cells to prevent the induction of inflammatory bowel disease that develops in these recipients (20, 21).
Collectively, our data are most consistent with a model in which CD4+CD25+ T cells play no role in the control of lymphopenia-induced proliferation, but that the proliferative response functions as a second signal that is required for the differentiation of CD4+CD25- autoreactive effector cells. Our ability to readily induce AIG in CD25-depleted, but not normal, animals by stimulation with the target Ag in IFA also suggests that strong TCR stimulation can provide the necessary second signal. We have not yet tested what other environmental inflammatory insults might be able to precipitate induction of autoimmunity in the CD25-depleted animal. Last, these results have important implications with regard to the therapeutic manipulation of CD4+CD25+ T cells in vivo. Depletion of CD4+CD25+ T cells greatly enhances the ability of the host to respond to immunization with a weak tumor vaccine (14, 15, 22). Depletion of CD4+CD25+ T cells might also be useful in the enhancement of immune responses to weak vaccines to infectious agents or to promote sterilizing immunity in the setting of chronic indolent infections. Although young adult euthymic mice appear to repopulate the CD4+CD25+ T cell pool within 2 mo following depletion, extrapolation of this finding to humans should be undertaken with caution in the absence of data on the capacity of the adult human thymus to produce CD4+CD25+ T cells.
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Footnotes |
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2 Abbreviations used in this paper: d3Tx, thymectomy on day 3 of life; AIG, autoimmune gastritis.
Received for publication March 18, 2002. Accepted for publication April 22, 2002.
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References |
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T. Barthlott, H. Moncrieffe, M. Veldhoen, C. J. Atkins, J. Christensen, A. O'Garra, and B. Stockinger CD25+CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production Int. Immunol., March 1, 2005; 17(3): 279 - 288. [Abstract] [Full Text] [PDF]
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P. A. Antony, C. A. Piccirillo, A. Akpinarli, S. E. Finkelstein, P. J. Speiss, D. R. Surman, D. C. Palmer, C.-C. Chan, C. A. Klebanoff, W. W. Overwijk, et al. CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells J. Immunol., March 1, 2005; 174(5): 2591 - 2601. [Abstract] [Full Text] [PDF]
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G. P. Morris, Y. Yan, C. S. David, and Y.-c. M. Kong H2A- and H2E-Derived CD4+CD25+ Regulatory T Cells: A Potential Role in Reciprocal Inhibition by Class II Genes in Autoimmune Thyroiditis J. Immunol., March 1, 2005; 174(5): 3111 - 3116. [Abstract] [Full Text] [PDF]
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B. Wei, P. Velazquez, O. Turovskaya, K. Spricher, R. Aranda, M. Kronenberg, L. Birnbaumer, and J. Braun Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets PNAS, February 8, 2005; 102(6): 2010 - 2015. [Abstract] [Full Text] [PDF]
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S. J. Prasad, K. J. Farrand, S. A. Matthews, J. H. Chang, R. S. McHugh, and F. Ronchese Dendritic Cells Loaded with Stressed Tumor Cells Elicit Long-Lasting Protective Tumor Immunity in Mice Depleted of CD4+CD25+ Regulatory T Cells J. Immunol., January 1, 2005; 174(1): 90 - 98. [Abstract] [Full Text] [PDF]
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N. Dikopoulos, A. Bertoletti, A. Kroger, H. Hauser, R. Schirmbeck, and J. Reimann Type I IFN Negatively Regulates CD8+ T Cell Responses through IL-10-Producing CD4+ T Regulatory 1 Cells J. Immunol., January 1, 2005; 174(1): 99 - 109. [Abstract] [Full Text] [PDF]
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 T. Dohi, K. Fujihashi, T. Koga, Y. Etani, N. Yoshino, Y. I. Kawamura, and J. R. McGhee CD4+CD45RBHi Interleukin-4 Defective T Cells Elicit Antral Gastritis and Duodenitis Am. J. Pathol., October 1, 2004; 165(4): 1257 - 1268. [Abstract] [Full Text] [PDF]
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N. Sarween, A. Chodos, C. Raykundalia, M. Khan, A. K. Abbas, and L. S. K. Walker CD4+CD25+ Cells Controlling a Pathogenic CD4 Response Inhibit Cytokine Differentiation, CXCR-3 Expression, and Tissue Invasion J. Immunol., September 1, 2004; 173(5): 2942 - 2951. [Abstract] [Full Text] [PDF]
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C. Vasu, B. S. Prabhakar, and M. J. Holterman Targeted CTLA-4 Engagement Induces CD4+CD25+CTLA-4high T Regulatory Cells with Target (Allo)antigen Specificity J. Immunol., August 15, 2004; 173(4): 2866 - 2876. [Abstract] [Full Text] [PDF]
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C. Baecher-Allan and D. A. Hafler Suppressor T Cells in Human Diseases J. Exp. Med., August 2, 2004; 200(3): 273 - 276. [Abstract] [Full Text] [PDF]
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K. V. Tarbell, S. Yamazaki, K. Olson, P. Toy, and R. M. Steinman CD25+ CD4+ T Cells, Expanded with Dendritic Cells Presenting a Single Autoantigenic Peptide, Suppress Autoimmune Diabetes J. Exp. Med., June 7, 2004; 199(11): 1467 - 1477. [Abstract] [Full Text] [PDF]
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M. Takeuchi, H. Keino, T. Kezuka, M. Usui, and O. Taguchi Immune Responses to Retinal Self-Antigens in CD25+CD4+ Regulatory T-Cell-Depleted Mice Invest. Ophthalmol. Vis. Sci., June 1, 2004; 45(6): 1879 - 1886. [Abstract] [Full Text] [PDF]
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M. K. Lee IV, D. J. Moore, B. P. Jarrett, M. M. Lian, S. Deng, X. Huang, J. W. Markmann, M. Chiaccio, C. F. Barker, A. J. Caton, et al. Promotion of Allograft Survival by CD4+CD25+ Regulatory T Cells: Evidence for In Vivo Inhibition of Effector Cell Proliferation J. Immunol., June 1, 2004; 172(11): 6539 - 6544. [Abstract] [Full Text] [PDF]
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 H Y Wu and N A Staines A deficiency of CD4+ CD25+ T cells permits the development of spontaneous lupus-like disease in mice, and can be reversed by induction of mucosal tolerance to histone peptide autoantigen Lupus, March 1, 2004; 13(3): 192 - 200. [Abstract] [PDF]
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D. Avichezer, R. S. Grajewski, C.-C. Chan, M. J. Mattapallil, P. B. Silver, J. A. Raber, G. I. Liou, B. Wiggert, G. M. Lewis, L. A. Donoso, et al. An Immunologically Privileged Retinal Antigen Elicits Tolerance: Major Role for Central Selection Mechanisms J. Exp. Med., December 1, 2003; 198(11): 1665 - 1676. [Abstract] [Full Text] [PDF]
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C. Cozzo, J. Larkin III, and A. J. Caton Cutting Edge: Self-Peptides Drive the Peripheral Expansion of CD4+CD25+ Regulatory T Cells J. Immunol., December 1, 2003; 171(11): 5678 - 5682. [Abstract] [Full Text] [PDF]
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G. Rajagopalan, Y. C. Kudva, L. Chen, L. Wen, and C. S. David Autoimmune diabetes in HLA-DR3/DQ8 transgenic mice expressing the co-stimulatory molecule B7-1 in the {beta} cells of islets of Langerhans Int. Immunol., September 1, 2003; 15(9): 1035 - 1044. [Abstract] [Full Text] [PDF]
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G. Oldenhove, M. de Heusch, G. Urbain-Vansanten, J. Urbain, C. Maliszewski, O. Leo, and M. Moser CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo J. Exp. Med., July 21, 2003; 198(2): 259 - 266. [Abstract] [Full Text] [PDF]
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 D. S. Game, M. P. Hernandez-Fuentes, A. N. Chaudhry, and R. I. Lechler CD4+CD25+ Regulatory T Cells Do Not Significantly Contribute to Direct Pathway Hyporesponsiveness in Stable Renal Transplant Patients J. Am. Soc. Nephrol., June 1, 2003; 14(6): 1652 - 1661. [Abstract] [Full Text] [PDF]
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Y. Y. Setiady, E. T. Samy, and K. S. K. Tung Maternal Autoantibody Triggers De Novo T Cell-Mediated Neonatal Autoimmune Disease J. Immunol., May 1, 2003; 170(9): 4656 - 4664. [Abstract] [Full Text] [PDF]
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C. Sharp, C. Thompson, E. T. Samy, R. Noelle, and K. S. K. Tung CD40 Ligand in Pathogenesis of Autoimmune Ovarian Disease of Day 3-Thymectomized Mice: Implication for CD40 Ligand Antibody Therapy J. Immunol., February 15, 2003; 170(4): 1667 - 1674. [Abstract] [Full Text] [PDF]
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 G. Rajagopalan, Y. C. Kudva, R. A. Flavell, and C. S. David Accelerated Diabetes in Rat Insulin Promoter-Tumor Necrosis Factor-{alpha} Transgenic Nonobese Diabetic Mice Lacking Major Histocompatibility Class II Molecules Diabetes, February 1, 2003; 52(2): 342 - 347. [Abstract] [Full Text] [PDF]
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P. A. Sieling, W. Chung, B. T. Duong, P. J. Godowski, and R. L. Modlin Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses J. Immunol., January 1, 2003; 170(1): 194 - 200. [Abstract] [Full Text] [PDF]
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H. Bagavant, C. Thompson, K. Ohno, Y. Setiady, and K. S. K. Tung Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease Int. Immunol., December 1, 2002; 14(12): 1397 - 1406. [Abstract] [Full Text] [PDF]
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, Animals positive for anti-parietal cell Abs.
C, Splenocytes from BALB/c mice, treated as in
B, were harvested 1 day after final Ab injection and
transferred to BALB/c nu/nu mice. Recipient mice were
analyzed 5–6 wk posttransfer for AIG.
