HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maurik, A. v. Articles by Jones, N. D. Search for Related Content PubMed PubMed Citation Articles by Maurik, A. v. Articles by Jones, N. D.

Cutting Edge: CD4⁺CD25⁺ Alloantigen-Specific Immunoregulatory Cells That Can Prevent CD8⁺ T Cell-Mediated Graft Rejection: Implications for Anti-CD154 Immunotherapy¹

Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Blockade of CD40-CD154 interactions can facilitate long-term allograft acceptance in selected rodent and in primate models, but, due to the ability of CD154-independent CD8⁺ T cells to initiate graft rejection, this strategy is not always effective. In this work we demonstrate that blockade of the CD40-CD154 pathway at the time of transplantation enables the generation of donor alloantigen-specific CD4⁺CD25⁺ regulatory T cells, and that if the regulatory cells are present in sufficient numbers they can suppress allograft rejection mediated by CD154-independent CD8⁺ T cells.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
The CD40-CD154 costimulation pathway plays a critical role in allograft rejection, because blockade of this interaction by administration of an anti-CD154 mAb has been shown to prolong the survival of allografts in a number of different animal models (1, 2, 3). However, in certain strains of mice, we and others have demonstrated that anti-CD154 mAb treatment failed to prevent CD8⁺ T cell-mediated rejection (4, 5, 6, 7, 8). Depletion of CD8⁺ T cells, using either a donor-specific transfusion or depleting anti-CD8 mAb in combination with anti-CD154 mAb therapy, was found to be required to induce long-term allograft acceptance. Interestingly, once allograft acceptance has been induced, a role for CD4⁺ regulatory T cells in the maintenance of graft function has been demonstrated (6, 8, 9, 10, 11). However, whether CD8⁺ T cell-mediated rejection can be influenced directly by regulatory T cells is unclear. Here we demonstrate that CD4⁺CD25⁺ regulatory cells that develop under conditions of CD40-CD154 blockade can inhibit CD154-resistant CD8⁺ T cell-mediated allograft rejection.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mice

CBA.Ca (CBA; H2^k), C57BL/10 (B10; H2^b), New Zealand White (NZW; H2^z), and BALB/c (H2^d) mice were purchased from Harlan (Bicester, U.K.). CBA.Ca recombinase-activating gene (RAG)³-1 knockout (CBA RAG^-/-) mice were a generous gift of Dr. D. Kioussis (Mill Hill, London, U.K.). BM3 TCR-transgenic mice (BM3; H2^k) were kindly provided by Prof. A. L. Mellor (Institute of Molecular Medicine and Genetics, Augusta, GA) and have been described previously (12). All mice were bred and housed in the Biomedical Services Unit of John Radcliffe Hospital (Oxford, U.K.) in accordance with the Animals (Scientific Procedure) Act 1986 of the U.K. All experiments were performed with 6- to 12-wk-old mice.

Surgical procedures

Heterotopic heart transplantation. Abdominal vascularized heterotopic heart transplants were performed essentially as documented by Corry et al. (13). Rejection was defined as a complete cessation of palpable cardiac contraction and was confirmed by direct visualization after laparotomy.

Skin transplantation. Full-thickness tail skin was transplanted to graft beds prepared on the left lateral thorax of anesthetized CBA RAG^-/- recipient mice. Graft rejection was defined as complete destruction of the skin.

Graft survival data were analyzed by the log rank method (14) using a statistical application developed and kindly provided by Dr. S. Cobbold (Sir William Dunn School of Pathology, Oxford, U.K.). Values of p <0.05 were considered statistically significant.

Ab treatment

CBA mice were treated with either anti-CD154 mAb (MR1; American Type Culture Collection, Manassas, VA) or hamster control Ab (hamster Ig (HIg); Jackson ImmunoResearch Laboratories, West Grove, PA) at 500 µg/day i.p. on days 0, 2, and 4 posttransplantation. For the depletion of CD8⁺ T cells, recipients were thymectomized 14 days before transplantation followed by anti-CD8 mAb treatment (100 µg i.p. on days -12 and -11 (hybridoma YTS169; a generous gift from Prof. H. Waldmann, Sir William Dunn School of Pathology)).

Cell purification and adoptive transfer (AT)

One hundred days posttransplantation, spleen cells from CBA mice were isolated by passing the tissue through a stainless steel mesh. Spleen cells were depleted of erythrocytes by osmotic shock, washed twice in RPMI, resuspended in sterile saline, and either injected i.v. or used to purify CD4⁺, CD8⁺, and CD4⁺CD25⁺ T cells using the MACS system (Miltenyi Biotec, Bergisch Gladbach, Germany) (15), typically to >95% purity. CD8⁺ T cells from BM3 TCR-transgenic mice were positively selected using this MACS system. For tracing experiments, CD8⁺ T cells from BM3 TCR-transgenic mice bred on a CBA RAG^-/- background were used. Transplantation procedures were performed 24 h after transfer.

Flow cytometric analysis

Leukocytes were first stained with anti-CD8-APC (BD PharMingen, Oxford, U.K.) and anti-clonotypic-TCR-biotin mAb (Ti98; kindly provided by Prof. A. L. Mellor). The biotin-labeled Ti98 mAb was developed with streptavidin-conjugated CyChrome (BD PharMingen). Finally, the samples were stained with anti-CD44-PE (IM7; BD PharMingen).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
We have previously demonstrated that fully MHC and minor histocompatibility Ag mismatched B10 cardiac allografts survive indefinitely (median survival time (MST) > 100 days) in CBA recipients after administration of an anti-CD154 mAb (MR1; 500 µg i.p. on days 0, 2, and 4) (4). First, we examined whether long-term acceptance of B10 cardiac allografts involved the generation of immunoregulatory mechanisms. Spleen leukocytes were prepared from MR1-treated CBA recipients that had accepted B10 cardiac allografts for >100 days (long-term survivors (LTS)) and 50 x 10⁶ unsorted cells adoptively transferred (AT) into naive secondary syngeneic CBA recipients. Fig. 1 shows that 55% of donor B10 hearts transplanted the following day were accepted for >100 days (MST > 100 days; n = 9), whereas NZW, third-party hearts were rejected acutely (MST = 11 days; n = 2). As expected, naive CBA recipients that were left untreated acutely rejected B10 cardiac allografts with a MST of 7 days (n = 6; data not shown). Transfer of 50 x 10⁶ unsorted cells >100 days posttransplant from mice that had received control HIg and a B10 cardiac allograft (grafts rejected with a MST of 7 days) failed to show any suppressive activity, as recipient mice rejected their grafts acutely (MST = 8 days; n = 4; data not shown).

View larger version (19K): [in this window] [in a new window]   FIGURE 1. Anti-CD154 mAb therapy enables the development of donor-specific CD4+ regulatory T cells. Spleens from MR1-treated CBA mice with well-functioning B10 cardiac allografts for >100 days were harvested and leukocytes were prepared. A total of 50 x 106 unsorted splenocytes or 10 x 106 purified CD4+ T cells were adoptively transferred (AT) into naive CBA recipients. The following day, these mice received a donor-type B10 or a third-party NZW cardiac allograft. *, p < 0.05.

To investigate the impact of these regulatory cells on CD8⁺ T cell-mediated responses to alloantigen we established an in vivo model in which the rejection of a skin allograft was mediated solely by TCR-transgenic CD8⁺ T cells specific for MHC class I alloantigen H2K^b (16).

First, we determined that AT of 1 x 10⁵ H2K^b-specific CD8⁺ TCR-transgenic T cells into CBA RAG^-/- mice was sufficient to reject a H2K^b+ (B10) skin allograft (Table I; MST = 16 days; n = 5). Unreconstituted CBA RAG^-/- mice all accepted B10 skin grafts over 50 days (data not shown). Next, we confirmed that anti-CD154 mAb treatment had no effect on the ability of this monospecific population of CD8⁺ T cells to mediate rejection of a B10 skin graft (MST = 16 days; n = 3; data not shown). The ability of the immunoregulatory T cells that developed in mice treated with anti-CD154 mAb at the time of transplantation to influence CD8⁺ T cell-mediated rejection was then examined by cotransferring increasing numbers of CD4⁺ or CD8⁺ T cells (Table I) and then CD4⁺CD25⁺ and CD4⁺CD25^- T cells (Fig. 2A) along with 1 x 10⁵ CD154-independent H2K^b-specific CD8⁺ T cells into CBA RAG^-/- recipients the day before skin grafting. Cotransfer of purified CD4⁺ T cells and CD4⁺CD25⁺ T cells prevented B10 skin allograft rejection mediated by H2K^b-specific CD8⁺ T cells in a dose-dependent manner (Table I and Fig. 2A, respectively). In contrast, purified CD8⁺ T cells or CD4⁺CD25^- T cells lacked any evidence of suppressive activity (Table I and Fig. 2A). Indeed, cotransfer of CD4⁺CD25^- T cells at a 10:1 ratio resulted in more rapid rejection of the B10 skin grafts (Fig. 2A).

View larger version (40K): [in this window] [in a new window]   FIGURE 2. CD4+CD25+ regulatory T cells inhibit CD8+ T cell-mediated skin graft rejection. A total of 1 x 105 H2Kb-specific CD8+ T cells were adoptively transferred into CBA RAG-/- recipients. Purified CD4+CD25+ or CD4+CD25- T cells from the spleens of MR1-treated CBA mice with LTS B10 or BALB/c cardiac allografts were cotransferred into reconstituted CBA RAG-/- mice. The following day, mice were transplanted with a H2Kb+ (B10) skin allograft or left untransplanted. A, Skin allograft survival was monitored. B, Spleen leukocytes were isolated 25 days after transplantation and the absolute number of H2Kb-specific CD8+ T cells was determined by flow cytometry using an anti-clonotypic TCR mAb, Ti98. *, NS. C, CD8+Ti98+ T cells were gated and analyzed for the expression of the marker of previous Ag exposure, CD44.

Finally, we evaluated whether the mechanism by which CD4⁺CD25⁺ T cells prevent H2K^b-specific CD8⁺ T cell-mediated skin allograft rejection was due to the deletion of CD8⁺ T cells. All CBA RAG^-/- mice were reconstituted with 1 x 10⁵ H2K^b-specific CD8⁺ T cells from BM3-RAG^-/- mice. One group was left untransplanted. Other mice received a B10 skin allograft either alone or in combination with 5 x 10⁵ CD4⁺CD25⁺ regulatory cells from B10 LTS. At 25 days posttransplantation—a time when all B10 skin allografts had been rejected in the groups that received 1 x 10⁵ H2K^b-specific CD8⁺ T cells only, but 80% of grafts on mice that received both CD8⁺ T cells and regulatory cells remained intact—the spleen and draining axillary lymph nodes were examined. It was found that cotransfer of CD4⁺CD25⁺ regulatory cells did not result in the deletion of alloantigen-specific CD8⁺ T cells (Fig. 2B). Similar numbers of CD8⁺Ti98⁺T cells were present in the spleens of untransplanted mice that only received H2K^b-specific CD8⁺ T cells (0.71 x 10⁴ ± 0.20 x 10⁴) and the group of reconstituted mice that have been transplanted after cotransfer of CD4⁺CD25⁺ T cells (0.91 x 10⁴ ± 0.40 x 10⁴). Similar findings were observed in the axillary lymph nodes (data not shown). Interestingly, a 5-fold higher number of CD8⁺Ti98⁺ T cells was found in the spleens of reconstituted CBA RAG^-/- mice that received a B10 transplant compared with transplanted CBA RAG^-/- mice that also received CD4⁺CD25⁺ regulatory T cells.

Recently, it has been demonstrated that CD4⁺CD25⁺ T cells have the capacity to control homeostatic expansion of both CD4⁺ and CD8⁺ T cell subsets (17, 18). However, control of homeostatic expansion of H2K^b-specific CD8⁺ T cells by the CD4⁺CD25⁺ T cells is unlikely to be the mechanism by which allograft rejection can be prevented in this model, because the cotransfer of CD4⁺CD25⁺ T cells taken from CBA mice with LTS BALB/c cardiac allografts failed to show any suppressive activity, indicating an alloantigen-specific component to the regulation (Fig. 2A).

Phenotype analysis revealed that, in the absence of a transplanted B10 skin allograft, 36.3 ± 4.4% of gated CD8⁺Ti98⁺ T cells expressed CD44, a marker of previous Ag exposure (Fig. 2C). As expected, after B10 skin allograft transplantation most CD8⁺Ti98⁺ T cells were positive for CD44 expression (93.0 ± 2.0%). In contrast, after B10 skin transplantation in the presence of CD4⁺CD25⁺ T cells, CD44 expression on gated CD8⁺Ti98⁺ T cells was reduced (57.3 ± 10.3%).

The finding that the majority of the regulated CD8⁺ T cells express the activation/memory marker CD44 (Fig. 2C) but are present in much lower numbers than in mice that did not receive regulatory cells (Fig. 2B) supports the hypothesis that suppression of graft rejection by CD4⁺CD25⁺ T cells is not due to deletion but may be attributed to the suppression of clonal expansion and/or the acquisition of effector function of alloreactive CD8⁺ T cells. Analysis at earlier time points is currently being performed to determine the precise response of the alloreactive CD8⁺ T cells under conditions of regulation.

This is the first report demonstrating directly that anti-CD154 mAb monotherapy at the time of transplantation enables the development of CD4⁺CD25⁺ T cells that have the capacity to inhibit CD154-resistant alloreactive CD8⁺ T cell-mediated rejection. These findings highlight the need for controlling the destructive response initiated by donor alloantigen-specific CD8⁺ T cells during the early phase of the rejection response. Our data suggest that this might be possible by establishing or infusing sufficient numbers of CD4⁺CD25⁺ donor alloantigen-specific regulatory T cells at the time of transplantation, by eliminating CD8⁺ T cells before transplantation, or by targeting costimulatory molecules that are used by CD8⁺ T cells (4, 5, 6, 7, 8). Clearly, once sufficient numbers of CD4⁺CD25⁺ regulatory T cells have developed, therapies targeting CD8⁺ T cell responses could be discontinued, because endogenously generated CD4⁺CD25⁺ regulatory cells have the capacity to control alloreactive CD8⁺ T cell responses.

	Footnotes

 
¹ This work was supported by the Roche Organ Transplant Research Foundation and The Wellcome Trust. A.v.M. holds a National Kidney Research Fund Studentship. K.J.W. holds a Royal Society-Wolfson Merit Award.

² Address correspondence and reprint requests to Dr. Nick D. Jones, Nuffield Department of Surgery, John Radcliffe Hospital, Oxford, OX3 9DU, U.K. E-mail address: nicholas.jones{at}surgery.ox.ac.uk

³ Abbreviations used in this paper: RAG, recombinase-activating gene; HIg, hamster Ig; AT, adoptive transfer; MST, median survival time; LTS, long-term survivor.

Received for publication May 20, 2002. Accepted for publication September 23, 2002.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Parker, D. C., D. L. Greiner, N. E. Phillips, M. C. Appel, A. W. Steele, F. H. Durie, R. J. Noelle, J. P. Mordes, A. A. Rossini. 1995. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc. Natl. Acad. Sci. USA 92:9560.[Abstract/Free Full Text]
2. Larsen, C. P., E. T. Elwood, D. Z. Alexander, S. C. Ritchie, R. Hendrix, C. Tucker-Burden, H. R. Cho, A. Aruffo, D. Hollenbaugh, P. S. Linsley, et al 1996. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381:434.[Medline]
3. Kirk, A. D., D. M. Harlan, N. N. Armstrong, T. A. Davis, Y. Dong, G. S. Gray, X. Hong, D. Thomas, J. H. J. Fechner, S. J. Knechtle. 1997. CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc. Natl. Acad. Sci. USA 94:8789.[Abstract/Free Full Text]
4. Jones, N. D., A. van Maurik, M. Hara, B. M. Spriewald, O. Witzke, P. J. Morris, K. J. Wood. 2000. CD40-CD40 ligand-independent activation of CD8⁺ T cells can trigger allograft rejection. J. Immunol. 165:1111.[Abstract/Free Full Text]
5. Trambley, J., A. W. Bingaman, A. Lin, E. T. Elwood, S. Y. Waitze, J. Ha, M. M. Durham, M. Corbascio, S. R. Cowan, T. C. Pearson, C. P. Larsen. 1999. Asialo GM1⁺CD8⁺ T cells play a critical role in costimulation blockade-resistant allograft rejection. J. Clin. Invest. 104:1715.[Medline]
6. Honey, K., S. P. Cobbold, H. Waldmann. 1999. CD40 ligand blockade induces CD4⁺ T cell tolerance and linked suppression. J. Immunol. 163:4805.[Abstract/Free Full Text]
7. Williams, M. A., J. Trambley, J. Ha, A. B. Adams, M. M. Durham, P. Rees, S. R. Cowan, T. C. Pearson, C. P. Larsen. 2000. Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts. J. Immunol. 165:6849.[Abstract/Free Full Text]
8. Iwakoshi, N. N., T. G. Markees, N. Turgeon, T. Thornley, A. Cuthbert, J. Leif, N. E. Phillips, J. P. Mordes, D. L. Greiner, A. A. Rossini. 2001. Skin allograft maintenance in a new synchimeric model system of tolerance. J. Immunol. 167:6623.[Abstract/Free Full Text]
9. Markees, T. G., N. E. Phillips, E. J. Gordon, R. J. Noelle, L. D. Shultz, J. P. Mordes, D. L. Greiner, A. A. Rossini. 1998. Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4⁺ T cells, interferon-, and CTLA4. J. Clin. Invest. 101:2446.[Medline]
10. Graca, L., K. Honey, E. Adams, S. P. Cobbold, H. Waldmann. 2000. Anti-CD154 therapeutic antibodies induce infectious transplantation tolerance. J. Immunol. 165:4783.[Abstract/Free Full Text]
11. Niimi, M., N. Shirasugi, Y. Ikeda, S. Kan, H. Takami, K. Hamano. 2001. Operational tolerance induced by pretreatment with donor dendritic cells under blockade of CD40 pathway. Transplantation 72:1556.[Medline]
12. Sponaas, A. M., P. D. Tomlinson, J. Antoniou, N. Auphan, C. Langlet, B. Malissen, A. M. Schmitt-Verhulst, A. L. Mellor. 1994. Induction of tolerance to self MHC class I molecules expressed under the control of milk protein or -globulin gene promoters. Int. Immunol. 6:227.
13. Corry, R. J., H. J. Winn, P. S. Russell. 1973. Primarily vascularized allografts of hearts in mice: the role of H-2D, H-2K, and non-H-2 antigens in rejection. Transplantation 16:343.[Medline]
14. Peto, R., P. C. Pik, P. Armitage, D. R. Cox, S. V. Howard, N. Mantal, K. M. Pherson, J. Peto, D. G. Smith. 1977. Design and analysis of randomised clinical trials which require prolonged observation of each patient. II Analysis and examples. Br. J. Cancer 35:1.[Medline]
15. Jones, N. D., A. van Maurik, M. Hara, B. J. Gilot, P. J. Morris, K. J. Wood. 1999. T-cell activation, proliferation, and memory after cardiac transplantation in vivo. Ann. Surg. 229:570.[Medline]
16. Jones, N. D., S. E. Turvey, A. van Maurik, M. Hara, C. I. Kingsley, C. H. Smith, A. L. Mellor, P. J. Morris, K. J. Wood. 2001. Differential susceptibility of heart, skin, and islet allografts to T cell-mediated rejection. J. Immunol. 166:2824.[Abstract/Free Full Text]
17. Annacker, O., R. Pimenta-Araujo, O. Burlen-Defranoux, T. C. Barbosa, A. Cumano, A. Bandeira. 2001. CD25⁺CD4⁺ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J. Immunol. 166:3008.[Abstract/Free Full Text]
18. Murakami, M., A. Sakamoto, J. Bender, J. Kappler, P. Marrack. 2002. CD25⁺CD4⁺ T cells contribute to the control of memory CD8⁺ T cells. Proc. Natl. Acad. Sci. USA 99:8832.[Abstract/Free Full Text]

This article has been cited by other articles:

				P. M. Porrett, X. Yuan, D. F. LaRosa, P. T. Walsh, J. Yang, W. Gao, P. Li, J. Zhang, J. M. Ansari, W. W. Hancock, et al. Mechanisms Underlying Blockade of Allograft Acceptance by TLR Ligands J. Immunol., August 1, 2008; 181(3): 1692 - 1699. [Abstract] [Full Text] [PDF]

				M. Carvalho-Gaspar, N. D. Jones, S. Luo, L. Martin, M. O. Brook, and K. J. Wood Location and Time-Dependent Control of Rejection by Regulatory T Cells Culminates in a Failure to Generate Memory T Cells J. Immunol., May 15, 2008; 180(10): 6640 - 6648. [Abstract] [Full Text] [PDF]

				M. Razmara, B. Hilliard, A. K. Ziarani, Y. H. Chen, and M. L. Tykocinski CTLA-4{middle dot}Ig converts naive CD4+CD25- T cells into CD4+CD25+ regulatory T cells Int. Immunol., April 1, 2008; 20(4): 471 - 483. [Abstract] [Full Text] [PDF]

				A. Demirkiran, B. M. Bosma, A. Kok, C. C. Baan, H. J. Metselaar, J. N. M. IJzermans, H. W. Tilanus, J. Kwekkeboom, and L. J. W. van der Laan Allosuppressive Donor CD4+CD25+ Regulatory T Cells Detach from the Graft and Circulate in Recipients after Liver Transplantation J. Immunol., May 15, 2007; 178(10): 6066 - 6072. [Abstract] [Full Text] [PDF]

				D. Golshayan, S. Jiang, J. Tsang, M. I. Garin, C. Mottet, and R. I. Lechler In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance Blood, January 15, 2007; 109(2): 827 - 835. [Abstract] [Full Text] [PDF]

				A. Toda and C. A. Piccirillo Development and function of naturally occurring CD4+CD25+ regulatory T cells J. Leukoc. Biol., September 1, 2006; 80(3): 458 - 470. [Abstract] [Full Text] [PDF]

				J. J. A. Coenen, H. J. P. M. Koenen, E. van Rijssen, L. Boon, I. Joosten, and L. B. Hilbrands CTLA-4 Engagement and Regulatory CD4+CD25+ T Cells Independently Control CD8+-Mediated Responses under Costimulation Blockade J. Immunol., May 1, 2006; 176(9): 5240 - 5246. [Abstract] [Full Text] [PDF]

				N. D. Jones, M. Carvalho-Gaspar, S. Luo, M. O. Brook, L. Martin, and K. J. Wood Effector and Memory CD8+ T Cells Can Be Generated in Response to Alloantigen Independently of CD4+ T Cell Help J. Immunol., February 15, 2006; 176(4): 2316 - 2323. [Abstract] [Full Text] [PDF]

				S. G. Zheng, L. Meng, J. H. Wang, M. Watanabe, M. L. Barr, D. V. Cramer, J. D. Gray, and D. A. Horwitz Transfer of regulatory T cells generated ex vivo modifies graft rejection through induction of tolerogenic CD4+CD25+ cells in the recipient Int. Immunol., February 1, 2006; 18(2): 279 - 289. [Abstract] [Full Text] [PDF]

				W Chalermskulrat, K P McKinnon, W J Brickey, I P Neuringer, R C Park, D G Sterka, B R Long, P McNeillie, R J Noelle, J P Ting, et al. Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance Thorax, January 1, 2006; 61(1): 61 - 67. [Abstract] [Full Text] [PDF]

				K. E. Lunsford, M. A. Koester, A. M. Eiring, P. H. Horne, D. Gao, and G. L. Bumgardner Targeting LFA-1 and CD154 Suppresses the In Vivo Activation and Development of Cytolytic (CD4-Independent) CD8+ T Cells J. Immunol., December 15, 2005; 175(12): 7855 - 7866. [Abstract] [Full Text] [PDF]

				F. Ghiringhelli, C. Menard, M. Terme, C. Flament, J. Taieb, N. Chaput, P. E. Puig, S. Novault, B. Escudier, E. Vivier, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-{beta}-dependent manner J. Exp. Med., October 17, 2005; 202(8): 1075 - 1085. [Abstract] [Full Text] [PDF]

				D. J. Mekala, R. S. Alli, and T. L. Geiger IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+ T lymphocytes PNAS, August 16, 2005; 102(33): 11817 - 11822. [Abstract] [Full Text] [PDF]

				S. A. Quezada, K. Bennett, B. R. Blazar, A. Y. Rudensky, S. Sakaguchi, and R. J. Noelle Analysis of the Underlying Cellular Mechanisms of Anti-CD154-Induced Graft Tolerance: The Interplay of Clonal Anergy and Immune Regulation J. Immunol., July 15, 2005; 175(2): 771 - 779. [Abstract] [Full Text] [PDF]

				M. Karim, G. Feng, K. J. Wood, and A. R. Bushell CD25+CD4+ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen-specific reactivation in vivo is critical for bystander regulation Blood, June 15, 2005; 105(12): 4871 - 4877. [Abstract] [Full Text] [PDF]

				D. T. Nardelli, J. P. Cloute, K. H. K. Luk, J. Torrealba, T. F. Warner, S. M. Callister, and R. F. Schell CD4+ CD25+ T Cells Prevent Arthritis Associated with Borrelia Vaccination and Infection Clin. Vaccine Immunol., June 1, 2005; 12(6): 786 - 792. [Abstract] [Full Text] [PDF]

				J. G. Heuer, T. Zhang, J. Zhao, C. Ding, M. Cramer, K. L. Justen, S. L. Vonderfecht, and S. Na Adoptive Transfer of In Vitro-Stimulated CD4+CD25+ Regulatory T Cells Increases Bacterial Clearance and Improves Survival in Polymicrobial Sepsis J. Immunol., June 1, 2005; 174(11): 7141 - 7146. [Abstract] [Full Text] [PDF]

				A. Bushell, E. Jones, A. Gallimore, and K. Wood The Generation of CD25+CD4+ Regulatory T Cells That Prevent Allograft Rejection Does Not Compromise Immunity to a Viral Pathogen J. Immunol., March 15, 2005; 174(6): 3290 - 3297. [Abstract] [Full Text] [PDF]

				D. J. Mekala and T. L. Geiger Immunotherapy of autoimmune encephalomyelitis with redirected CD4+CD25+ T lymphocytes Blood, March 1, 2005; 105(5): 2090 - 2092. [Abstract] [Full Text] [PDF]

				B. Metzler, P. Gfeller, M. Bigaud, J. Li, G. Wieczorek, C. Heusser, P. Lake, and A. Katopodis Combinations of Anti-LFA-1, Everolimus, Anti-CD40 Ligand, and Allogeneic Bone Marrow Induce Central Transplantation Tolerance through Hemopoietic Chimerism, Including Protection from Chronic Heart Allograft Rejection J. Immunol., December 1, 2004; 173(11): 7025 - 7036. [Abstract] [Full Text] [PDF]

				L. Weiss, V. Donkova-Petrini, L. Caccavelli, M. Balbo, C. Carbonneil, and Y. Levy Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients Blood, November 15, 2004; 104(10): 3249 - 3256. [Abstract] [Full Text] [PDF]

				G. Zheng, B. Wang, and A. Chen The 4-1BB Costimulation Augments the Proliferation of CD4+CD25+ Regulatory T Cells J. Immunol., August 15, 2004; 173(4): 2428 - 2434. [Abstract] [Full Text] [PDF]

				L. Graca, A. Le Moine, C.-Y. Lin, P. J. Fairchild, S. P. Cobbold, and H. Waldmann Donor-specific transplantation tolerance: The paradoxical behavior of CD4+CD25+ T cells PNAS, July 6, 2004; 101(27): 10122 - 10126. [Abstract] [Full Text] [PDF]

				M. R. Karlsson, J. Rugtveit, and P. Brandtzaeg Allergen-responsive CD4+CD25+ Regulatory T Cells in Children who Have Outgrown Cow's Milk Allergy J. Exp. Med., June 21, 2004; 199(12): 1679 - 1688. [Abstract] [Full Text] [PDF]

				Q. Tang, K. J. Henriksen, M. Bi, E. B. Finger, G. Szot, J. Ye, E. L. Masteller, H. McDevitt, M. Bonyhadi, and J. A. Bluestone In Vitro-expanded Antigen-specific Regulatory T Cells Suppress Autoimmune Diabetes J. Exp. Med., June 7, 2004; 199(11): 1455 - 1465. [Abstract] [Full Text] [PDF]

				T. L. Sumpter and D. S. Wilkes Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1129 - L1139. [Abstract] [Full Text] [PDF]

				O. Joffre, N. Gorsse, P. Romagnoli, D. Hudrisier, and J. P. M. van Meerwijk Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes Blood, June 1, 2004; 103(11): 4216 - 4221. [Abstract] [Full Text] [PDF]

				B. K. Choi, J. S. Bae, E. M. Choi, W. J. Kang, S. Sakaguchi, D. S. Vinay, and B. S. Kwon 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells J. Leukoc. Biol., May 1, 2004; 75(5): 785 - 791. [Abstract] [Full Text] [PDF]

				A. van Maurik, B. F. de St. Groth, K. J. Wood, and N. D. Jones Dependency of Direct Pathway CD4+ T Cells on CD40-CD154 Costimulation Is Determined by Nature and Microenvironment of Primary Contact with Alloantigen J. Immunol., February 15, 2004; 172(4): 2163 - 2170. [Abstract] [Full Text] [PDF]

				M. Stanzani, S. L. R. Martins, R. M. Saliba, L. S. St. John, S. Bryan, D. Couriel, J. McMannis, R. E. Champlin, J. J. Molldrem, and K. V. Komanduri CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans Blood, February 1, 2004; 103(3): 1140 - 1146. [Abstract] [Full Text] [PDF]

				M. Karim, C. I. Kingsley, A. R. Bushell, B. S. Sawitzki, and K. J. Wood Alloantigen-Induced CD25+CD4+ Regulatory T Cells Can Develop In Vivo from CD25-CD4+ Precursors in a Thymus-Independent Process J. Immunol., January 15, 2004; 172(2): 923 - 928. [Abstract] [Full Text] [PDF]

				B. Dubois, L. Chapat, A. Goubier, M. Papiernik, J.-F. Nicolas, and D. Kaiserlian Innate CD4+CD25+ regulatory T cells are required for oral tolerance and inhibition of CD8+ T cells mediating skin inflammation Blood, November 1, 2003; 102(9): 3295 - 3301. [Abstract] [Full Text] [PDF]

				S. Yamazaki, T. Iyoda, K. Tarbell, K. Olson, K. Velinzon, K. Inaba, and R. M. Steinman Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells J. Exp. Med., July 21, 2003; 198(2): 235 - 247. [Abstract] [Full Text] [PDF]

				T. Pearson, T. G. Markees, D. V. Serreze, M. A. Pierce, M. P. Marron, L. S. Wicker, L. B. Peterson, L. D. Shultz, J. P. Mordes, A. A. Rossini, et al. Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice J. Immunol., July 1, 2003; 171(1): 185 - 195. [Abstract] [Full Text] [PDF]

				N. E. Phillips, T. G. Markees, J. P. Mordes, D. L. Greiner, and A. A. Rossini Blockade of CD40-Mediated Signaling Is Sufficient for Inducing Islet But Not Skin Transplantation Tolerance J. Immunol., March 15, 2003; 170(6): 3015 - 3023. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager