The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wise, M. P.
Right arrow Articles by Waldmann, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wise, M. P.
Right arrow Articles by Waldmann, H.
The Journal of Immunology, 1998, 161: 5813-5816.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Linked Suppression of Skin Graft Rejection Can Operate Through Indirect Recognition1

Matt P. Wise, Frederike Bemelman, Steve P. Cobbold and Herman Waldmann2

Dunn School of Pathology, South Parks Road, Oxford, United Kingdom


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Adult mice can be rendered immunologically tolerant of allogeneic tissues if transplanted under cover of mAbs to CD4 and CD8. Tolerance generated in this manner is characterized by the presence of regulatory CD4+ T cells that can recruit naive T cells to become tolerant also through "infectious tolerance." Regulatory CD4+ T cells can also suppress rejection of third party transplant Ags provided they are expressed on the same graft as the tolerated Ags. This process of linked suppression can act across whole MHC barriers and represents a powerful mechanism with therapeutic potential. Tolerance can also be induced to reprocessed minor transplantation Ags presented through host APCs (indirect recognition). We here demonstrate that linked suppression can also be induced through the indirect pathway. This finding may be important in the development of transplantation tolerance in the clinic.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Monoclonal Abs to CD4 and CD8 have proved powerful tools for inducing tolerance to various tissues in rodents (1). Tolerance is maintained by regulatory CD4+ T cells that not only suppress rejection by naive T cells, but co-opt them to become tolerant too (2). Tolerance is also extended to third party transplant Ags, even to MHC-encoded Ags, provided they are expressed on the same graft as the tolerated Ags (3, 4, 5). Thus, CBA/Ca mice tolerant of B10.BR minor Ags following mAb therapy will normally reject MHC class I disparate CBK skin transplants, but accept or show delayed rejection of (B10.BR x CBK)F1 grafts. Mice with grafts surviving long-term subsequently accept CBK skin, demonstrating that tolerance has been established peripherally to this "linked" Ag (3). This effect is not due to dilution of Ag in the F1 donors because (CBA/Ca x CBK)F1 is rapidly rejected. The mechanisms underlying such "linked suppression" must be powerful ones, as tolerance can be extended to whole MHC disparities when applied to cardiac transplantation (4, 5). It would be most helpful for purposes of inducing clinical transplantation tolerance to understand the nature of the Ags and the mode of their presentation required to drive linked suppression.

In 1989 Qin et al. (6) made a surprising observation of "split tolerance" following the transplantation of allogeneic B10.BR (H-2k) bone marrow into BALB/c (H-2d) recipients under cover of CD4 and CD8 mAb. These animals were later found to reject skin grafts from B10.BR mice rapidly (median survival time (MST)3 = 9.8 days), whereas skin from B10.D2 (H-2d) mice (which like B10.BR also derive their minor Ags from the same C57BL (Black) genetic background), survived much longer (MST = 56 days). The interpretation that was offered was that some skin minors of the Black background (B10.BR) origin had been reprocessed on host MHC (H-2d), leading to partial tolerance to this combination. Subsequently, Davies et al. (3) demonstrated that CD4 and CD8 Ab facilitated tolerance could operate through indirect Ag presentation on host APCs by tolerizing (CBA/Ca x BALB/c)F1 (H-2kxd) mice by exposure to either B10.BR (H-2k) or B10.D2 (H-2d) skin. Animals transplanted with B10.BR under cover of mAb treatment would subsequently accept either B10.BR (H-2k) or B10.D2 (H-2d) grafts (and vice versa). Clearly, B10 minors would have to be presented on host APCs for this effect to be to observed.

In as far as we know that tolerance in these models involves CD4-T cell-mediated regulation through linked suppression and infectious tolerance, we wished to establish whether this form of regulation could involve Ags processed through the indirect pathway. We here show for the first time that linked suppression of transplant rejection does indeed exploit this route, and discuss the therapeutic implications of the findings.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Mice

B10.D2 (H-2d) mice were supplied by Harlan Olac, Bicester, U.K. (CBA/Ca x BALB/c)F1 (H-2kxd), (B10.BR x AKR)F1 (H-2k), (CBA/Ca x AKR)F1 (H-2k), and B10.BR (H-2k) mice were bred and maintained at the Dunn School of Pathology, Oxford University. All animals were treated in accordance with the Home Office Animals (Scientific Procedures) Act of 1986.

Monoclonal Abs

All hybridomas were grown in hollow fiber bioreactors in our own laboratory. Culture supernatant was withdrawn from the "harvest" side of the bioreactor and purified further by ammonium sulfate precipitation. All Ab preparations were dialyzed into PBS and adjusted to 10 mg/ml. The following hybridomas were used against murine CD4, YTS 177.9.6 (7) (rat IgG2a), or CD8, YTS 105.18.10 (7) (rat IgG2a), YTS 169.4.2.1 (8) (rat IgG2b), and YTS 156.7.7 (8) (rat IgG2b).

Surgery and tolerance induction

Skin grafting was conducted as described previously (3): in brief donor tail skin (~1 cm2) was grafted onto the flank of recipient euthymic mice which were then covered with impregnated and fulminated gauze. A plaster cast was applied and secured with an autoclip. Bandaging was removed 8 days later, and grafts were observed on alternate days for rejection. Animals were regrafted as specified in the text on the contralateral flank using the same technique. Grafts were scored as being rejected when no viable tissue was visible. Statistical analysis of graft survival was by the log-rank method (9).

Tolerance was induced by giving three i.p. injections of CD4 and CD8 mAb over a period of 1 wk starting on the day of transplantation. Mice received either 1 mg each of YTS 177.9.6 and YTS 105.18.10 per injection or 0.5 mg YTS 177.9.6 plus 0.25 mg YTS 169.4.2.1 and 0.25 mg YTS 156.7.7 per injection as specified in the text.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Linked suppression can operate through indirect recognition

(CBA/Ca x BALB/c)F1 mice can be made tolerant of minor mismatched skin grafts using nondepleting CD4 and CD8 mAbs administered at the time of transplantation. This has been shown to involve reprocessing of minors on host APCs (3). Recipients tolerant of B10.BR (H-2k) will therefore accept either B10.BR or B10.D2 (H-2d) skin grafts when retransplanted at a later date. We asked if linked suppression could also operate through recognition of reprocessed minor Ags in host APCs.

Euthymic (CBA/Ca x BALB/c)F1 mice were transplanted with either B10.BR or B10.D2 skin and given three injections of nondepleting CD4 and CD8 mAb (YTS 177.9.6 and YTS 105.18.10). These tolerant recipients were retransplanted after eighty days with either (B10.BR x AKR)F1 or (CBA/Ca x AKR)F1 skin. All animals rejected (CBA/Ca x AKR)F1 skin as expected, illustrating that the recipients were immunocompetent following previous Ab treatment (Fig. 1Go). In contrast, mice tolerant of B10.BR accepted (B10.BR x AKR)F1 transplants (MST > 56 days) confirming that linked suppression can operate to skin minors (AKR) in euthymic animals. Failure to reject the F1 skin was not the result of "diluted" Ag, because mice tolerant of B10.BR reject (CBA/Ca x AKR)F1 grafts. However, recipients tolerant of B10.D2 (H-2d) also demonstrated linked suppression of (B10.BR x AKR)F1 skin grafts (H-2k) (Fig. 1Go). This finding means that T cells effecting linked suppression to the F1 graft must therefore be operating through B10 minors presented on host APCs that express both H-2k and H-2d; i.e., minors that have been recognized through the indirect pathway.



View larger version (16K):
[in this window]
[in a new window]
  		FIGURE 1. Linked suppression can operate through the indirect pathway. Adult (CBA/Ca x BALB/c)F1 mice (H-2kxd) were tolerized to either B10.BR (H-2k) or B10.D2 (H-2d) skin grafts by administering three injections of mAb to murine CD4 and CD8 over a period of 1 wk as specified in Materials and Methods. Mice tolerant of B10.BR (H-2k) were retransplanted at 80 days with either (B10.BR x AKR)F1 (H-2k) (open squares; MST > 56 days, n = 9) or (CBA/Ca x AKR)F1 (H-2k) (filled squares; MST = 21 days, n = 8) skin (p < = 0.00008). Animals tolerant of B10.D2 (H-2d) were regrafted with (B10.BR x AKR)F1 (open circles; MST > 56 days, n = 12) or (CBA/Ca x AKR)F1 (filled circles; MST = 25 days, n = 8) skin (p < = 0.00002). Linked suppression to AKR minors can therefore operate through the indirect pathway. Mice transplanted with (CBA/Ca x AKR)F1 skin kept their first tolerant graft intact throughout the experiment.

 
Linked suppression operating through indirect recognition does not require CD8 T cells to be present at induction

Tolerance facilitated by CD4 and CD8 mAbs is characterized by the presence of regulatory CD4 T cells. CD8 T cells may also recognize minor graft Ags reprocessed on host APCs in the context of MHC class I (10). Therefore, we asked if the induction of tolerance to reprocessed minors required the presence of CD8 T cells. Euthymic (CBA/Ca x BALB/c)F1 mice were grafted with B10.D2 skin under cover of nondepleting CD4 mAb (YTS 177.9.6) and a synergistic pair of CD8 depleting mAbs (YTS 169.4.2.1 and YTS 156.7.7). Control animals received Ab alone but no graft.

Six weeks later, animals that had only received Ab treatment, but no tolerogen, were competent to reject B10.D2 or (B10.BR x AKR)F1 skin (Fig. 2Go). Animals that had received Abs with B10.D2 skin (tolerogen) were retransplanted with either control (CBA/Ca x AKR)F1 skin, which was rejected, or with (B10.BR x AKR)F1 skin, which was accepted (Fig. 2Go). Therefore, CD8 T cells are not required for this regulatory process, and we must infer that the CD4 T cell subset previously implicated in infectious tolerance (2), must be responsible for effecting linked suppression to AKR minors through recognition of reprocessed minors on host APCs. (As rejection of minor mismatched grafts in this strain combination is mediated by CD4 T cells (11), the reverse experiment of CD4 T cell ablation would not be revealing.)



View larger version (17K):
[in this window]
[in a new window]
  		FIGURE 2. Linked suppression operating through indirect recognition does not require CD8 T cells to be present at induction. Adult (CBA/Ca x BALB/c)F1 mice (H-2kxd) were given three injections of depleting CD8 and nondepleting CD4 mAb as specified in Materials and Methods and then transplanted 6 wk later with either B10.D2 (filled circles; MST = 16 days, n = 8) or (B10.BR x AKR)F1 (open circles; MST = 18 days, n = 8) skin grafts. Two additional groups of mice were made tolerant of B10.D2 skin by transplanting under cover of Ab therapy as above. Six weeks later tolerant animals were retransplanted with either (CBA/Ca x AKR)F1 (open squares; MST = 35 days, n = 8) or (B10.BR x AKR)F1 (filled squares; MST > 60 days, n = 8) skin (p < = 0.00007). B10.D2 skin grafts remained healthy in both sets of mice. Linked suppression to AKR minors operating through the indirect pathway does not require CD8 T cells to be present at the induction of tolerance.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The realization that transplanted tissues provoke rejection through both the direct and indirect Ag processing pathways has major implications for strategies of tolerance induction, in so far as it requires us to consider how therapeutic tolerance can embrace both forms of donor Ag. The extent to which the indirect pathway of Ag presentation contributes to graft rejection varies depending on the origin of the donor tissue. For example, skin transplants from MHC class I and II knockout mice are rejected as rapidly as grafts from wild-type donors (12), while heart grafts can survive indefinitely (13). It has also been suggested that chronic rejection is driven through reprocessing of donor Ags on host APCs (14).

Short-term therapy with mAbs to CD4 and CD8 has proven to be a powerful tool for inducing tolerance to many grafted tissues in rodent models (1). Tolerance is characterized by regulatory CD4 T cells that can suppress rejection by naive T cells and even recruit naive T cells to become tolerant too (2). Short-term Ab therapy does not lead to global defects in immunity as evidenced by a return of normal immune responses to third party Ags. However, it has been known for some time that tolerance generated to one Ag may suppress the response to unrelated Ags expressed on the same cell surface (15) or graft (16, 17). Regulatory CD4 T cells generated after CD4 and CD8 mAb therapy can also effect suppression of third party Ags provided that they are expressed on the same tissue as the tolerated Ags (3, 4, 5). This linked suppression is sufficiently powerful to extend not only to minor Ags as the linked Ag but whole MHC disparities (4, 5). Linked suppression can also lead to tolerance of the third party graft, as shown for the MHC class I molecule Kb expressed as a transgene on skin (3), whereas Ab therapy combined with the Kb incompatible graft fails (M. P. Wise, unpublished observation), implying that one is dealing with an extremely potent form of regulation which one might potentially exploit clinically.

Tolerance to minor Ags can occur through indirect presentation alone (3, 18), in other words recipient T cells may be tolerized by donor Ag that has been shed from a graft, captured by host APCs where it is processed and presented. Here, for the first time, we make the important observation that linked suppression can also operate through Ag presentation via the indirect pathway. This process does not require the participation of CD8 T cells during induction, implying that regulatory CD4 T cells are sufficient. Presumably, then these regulatory T cells recognize reprocessed Ag in the context of recipient MHC class II. The finding that parenchymal self Ags are presented for tolerance to CD4 T cells on bone marrow-derived APCs (19) suggests that linked suppression could also play a role in maintaining self tolerance. Autoimmunity, which might otherwise be triggered by the appearance of previously sequestered Ags, would be prevented by CD4 T cells tolerant of peripheral self Ags (20, 21, 22, 23) acting on local APCs.

The finding that linked suppression can function through the indirect pathway offers an explanation for the previous finding of "split tolerance" by Qin et al. (6). It may also explain how linked suppression operates across whole MHC plus minors barriers (4, 5) to cardiac allografts, through continuous reprocessing of donor Ag on host APCs, once the donor APCs are lost soon after transplantation (24). The requirement for both tolerated and linked Ags to be on the same tissue implies that tolerant and potentially aggressive T cells are focussed onto the same APC, and this is supported by in vitro data (15, 25, 26). Whether tolerant T cells regulate responses to third party Ags through local competition of cytokines and/or costimulation, or have temporally dissociated effects on the APCs ability to immunize (27, 28, 29) or tolerize (30), remain to be elucidated (Fig. 3Go).



View larger version (20K):
[in this window]
[in a new window]
  		FIGURE 3. Linked suppression through indirect recognition. Top, (CBA/Ca x BALB/c)F1 mice made tolerant of B10.D2 skin grafts with mAb to CD4 and CD8 are also tolerant of B10.BR skin (3) and so must have been tolerized to B10 minors reprocesed on I-Ak and I-Ek in addition to I-Ad and I-Ed. Bottom, (CBA/Ca x BALB/c)F1 mice tolerant of B10.D2 skin show linked suppression to (B10.BR x AKR)F1 grafts. Tolerant CD4 T cells recognizing reprocessed B10 minors in the context of I-Ak and I-Ek suppress rejection of naive T cells recognizing AKR minors. CD4 T cell mediated suppression may operate through direct interaction with naive T cells (competition for cytokines, costimulation, or production of cytokines co-opting cells to become tolerant) or by down-regulating the immunostimulatory capacity of APCs (as indicated by arrows). Tolerant T cells may act through either mechanism or by both acting synergistically.

 
One would like to harness regulatory CD4 T cells to promote therapeutic tolerance. In considering transplants and autoimmune disease, it is often the case that the number of target Ags is large, and many remain unidentified. The notion that tolerance need not be established to every possible Ag at the outset offers greater therapeutic flexibility. Currently, the supply and demand of donor organs for transplantation means that both the timing of surgery and the incompatibilities involved remain unknown. Knowledge of common immunodominant minors (31) or xenoantigens would allow one to establish regulatory T cells at a period of clinical stability before transplantation. The observation that linked suppression is effective when Ag is presented through the indirect pathway means that it may be given in any form that can undergo reprocessing in the host.

A two-step strategy targeting common Ags has many potential benefits in transplantation. Regulatory T cells can be initiated at a time of relative clinical stability, then maintained and reinforced by further Ag administration. In addition to improved long-term graft survival, a further benefit may be to allow reduced levels of drug immunosuppression, thereby reducing patient morbidity and mortality. Indirect presentation may be important in driving chronic rejection (14), and so any strategy that tolerizes through this route may have beneficial effects on late graft loss.

Finally, we consider it unlikely that linked suppression through the indirect pathway is idiosyncratic to the particular model systems we use, nor just to rodents. Linked suppression acting through the indirect pathway may well be the explanation for the so called blood transfusion effect so well documented in rodents (32, 33) and humans (34). Linked suppression has been demonstrated with human T cells in vitro (25, 26) for both resting and memory human T cells. The harnessing of linked suppression induced through the indirect pathway would therefore appear to offer a realistic strategy for immunotherapy in humans.


   Footnotes
 
1 This work was supported by grants from the Medical Research Council U.K. and by European Union Grant PL962151. Back

2 Address correspondence and reprint requests to Herman Waldmann, Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, U.K. E-mail address: Back

3 Abbreviation used in this paper: MST, median survival time. Back

Received for publication July 8, 1998. Accepted for publication September 29, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Waldmann, H., S. P. Cobbold. 1998. How do Monoclonal antibodies induce tolerance? A role for infectious tolerance?. Annu. Rev. Immunol. 16:619.[Medline]
  2. Qin, S., S. P. Cobbold, H. Pope, J. Elliot, D. Kioussis, J. Davies, H. Waldmann. 1993. Infectious transplantation tolerance. Science 259:974.[Abstract]
  3. Davies, J. D., L. Y. W. Leong, A. Mellor, S. P. Cobbold, H. Waldmann. 1996. T cell suppression in transplantation tolerance through linked recognition. J. Immunol. 156:3602.[Abstract]
  4. Chen, Z. K., S. P. Cobbold, H. Waldmann, S. Metcalfe. 1996. Amplification of natural regulatory immune mechanisms for transplantation tolerance. Transplantation 62:1200.[Medline]
  5. Wong, W., P. J. Morris, K. J. Wood. 1997. Pretransplant administration of a single donor class I MHC molecule is sufficient for the indefinite survival of fully allogeneic cardiac allografts. Transplantation 63:1490.[Medline]
  6. Qin, S., S. P. Cobbold, R. Benjamin, H. Waldmann. 1989. Induction of classical transplantation tolerance in the adult. J. Exp. Med. 169:779.[Abstract/Free Full Text]
  7. Qin, S., M. Wise, S. P. Cobbold, L. Leong, Y.-C. Kong, J. R. Parnes, H. Waldmann. 1990. Induction of tolerance in peripheral T cells with monoclonal antibodies. Eur. J. Immunol. 20:2737.[Medline]
  8. Cobbold, S. P., A. Jayasuriya, A. Nash, T. D. Prospero, H. Waldmann. 1984. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312:548.[Medline]
  9. Peto, R., M. C. Pike, P. Armitage, N. E. Breslow, D. R. Cox, S. V. Howard, N. Mantel, K. McPherson, J. Peto, P. G. Smith. 1977. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br. J Cancer 35:1.[Medline]
  10. Oukka, M., M. Galou, Y. Belkaid, V. Tricotet, N. Riche, M. Reynes, K. Kosmatopoulos. 1997. MHC class I presentation of exogenously aquired minor alloantigens initiates skin allograft rejection. Eur. J. Immunol. 27:3499.[Medline]
  11. Cobbold, S., H. Waldmann. 1986. Skin allograft rejection by L3/T4+ and LYT-2+ T cell subsets. Transplantation 41:634.[Medline]
  12. Auchincloss, H., R. Lee, S. Shea, J. S. Markowitz, M. J. Grusby, L. H. Glimcher. 1993. The role of "indirect" recognition in initiating rejection of skin grafts from MHC class II deficient mice. Proc. Natl. Acad. Sci. 90:3373.[Abstract/Free Full Text]
  13. Campos, L., A. Naji, B. C. Deli, J. H. Kern, J. I. Kim, C. F. Barker, J. F. Markmann. 1995. Survival of MHC deficient mouse heterotopic cardiac allografts. Transplantation 59:187.[Medline]
  14. Vella, J. P., L. Vos, C. B. Carpenter, M. H. Sayegh. 1997. Role of indirect allorecognition in experimental late acute rejection. Transplantation 64:1823.[Medline]
  15. Holan, V., N. A. Mitchenson. 1983. Haplotype specific suppressor T cells mediating linked suppression of immune responses elicited by third party H-2 alloantigens. Eur. J. Immunol. 13:652.[Medline]
  16. Madsen, J. C., R. A. Superina, K. J. Wood, P. J. Morris. 1988. Immunological unresponsiveness induced by recipient cells transfected with donor MHC genes. Nature 332:161.[Medline]
  17. Wong, W., P. J. Morris, K. J. Wood. 1996. Syngeneic bone marrow expressing a single donor class I MHC molecule permits acceptance of a fully allogeneic cardiac allograft. Transplantation 62:1462.[Medline]
  18. Tomita, Y., K. Nomoto. 1990. Induction of tolerance to non-H-2 alloantigens is not restricted by the MHC molecules expressed on the donor cells in cyclophosphamide induced tolerance. Immunobiology 181:430.[Medline]
  19. Adler, A. J., D. W. Marsh, G. S. Yochum, J. L. Guzzo, A. Nigam, W. G. Nelson, D. M. Pardoll. 1998. CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow derived antigen presenting cells. J. Exp. Med. 187:1555.[Abstract/Free Full Text]
  20. Fowell, D., D. Mason. 1993. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177:627.[Abstract/Free Full Text]
  21. Saoudi, A., B. Seddon, D. Fowell, D. Mason. 1996. The thymus contains a high frequency of cells that prevent autoimmune diabetes on transfer into pre-diabetic recipients. J. Exp. Med. 184:2393.[Abstract/Free Full Text]
  22. Modigliani, Y., P. Pereira, V. Thomas-Vaslin, J. Salaun, O. Burlen-Defranoux, A. Coutinho, N. Le Douarin, A. Bandeira. 1995. Regulatory T cells in thymic epithelium induced tolerance. I. Suppression of mature peripheral non-tolerant T cells. Eur. J. Immunol. 25:2563.[Medline]
  23. Modigliani, Y., A. Coutinho, P. Pereira, N. Le Douarin, V. Thomas-Vaslin, O. Burlen-Defranoux, J. Salaun, A. Bandeira. 1996. Establishment of tissue specific tolerance is driven by regulatory T cells selected by thymic epithelium. Eur. J. Immunol. 26:1807.[Medline]
  24. Larsen, C. P., P. J. Morris, J. Austyn. 1990. Migration of dendritic leukocytes from cardiac allografts into host spleens: a novel pathway for the initiation of rejection. J. Exp. Med. 171:307.[Abstract/Free Full Text]
  25. Frasca, L., P. Carmichael, R. Lechler, G. Lombardi. 1997. Anergic T cells effect linked suppression. Eur. J. Immunol. 27:3191.[Medline]
  26. Marelli-Berg, F. M., A. Weetman, L. Frasca, S. J. Deacock, N. Imani, G. Lombardi, R. I. Lechler. 1997. Antigen presentation by epithelial cells induces anergic immunoregulatory CD45RO+ T cells and deletion of CD45RA+ T cells. J. Immunol. 159:5853.[Abstract]
  27. Ridge, J. P., F. Di Rosa, P. A. Matzinger. 1998. Conditioned dendritic cell can be a temporal bridge between a CD4+ T helper and a T killer cell. Nature 393:474.[Medline]
  28. Bennet, S. R. M., F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. A. P. Miller., W. R. Heath. 1998. Help for cytotoxic T cell responses is mediated by CD40 signalling. Nature 193:478.
  29. Schoenberger, S. P., R. E. M. Toes, E. I. H. van der Voort, R. Offringa, C. J. M. Melief. 1998. T cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480.[Medline]
  30. Gorczynski, R. M., Z. Cohen, X.-M. Fu, Z. Hua Y. Sun, Z. Chen. 1996. Interleukin-13, in combination with anti-interleukin-12, increases graft prolongation after portal venous immunization with cultured allogeneic bone-marrow derived dendritic cells. Transplantation 62:1592.[Medline]
  31. Perreault, C., D. C. Roy, C. Fortin. 1998. Immunodominant minor histocompatibility antigens: the major ones. Immunol. Today 19:69.[Medline]
  32. Quigley, R. L., K. J. Wood, P. J. Morris. 1989. Transfusion induces blood donor specific suppressor cells. J. Immunol. 142:463.[Abstract]
  33. Bushell, A., P. J. Morris, K. J. Wood. 1995. Transplantation tolerance induced by antigen pretreatment and depleting anti-CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response. Eur. J. Immunol. 25:2643.[Medline]
  34. Opelz, G., D. P. S. Sengar, M. R. Mickey, P. I. Terasaki. 1973. Effect of blood transfusions on subsequent kidney transplants. Transplant. Proc. 5:253.[Medline]



This article has been cited by other articles:


Home page
 Endocr. Rev.Home page
X. Huang, D. J. Moore, R. J. Ketchum, C. S. Nunemaker, B. Kovatchev, A. L. McCall, and K. L. Brayman
Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation
Endocr. Rev., August 1, 2008; 29(5): 603 - 630.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
P. Verginis, K. A. McLaughlin, K. W. Wucherpfennig, H. von Boehmer, and I. Apostolou
Induction of antigen-specific regulatory T cells in wild-type mice: Visualization and targets of suppression
PNAS, March 4, 2008; 105(9): 3479 - 3484.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. A. Kapp, K. Honjo, L. M. Kapp, K. Goldsmith, and R. P. Bucy
Antigen, in the Presence of TGF-beta, Induces Up-Regulation of FoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses
J. Immunol., August 15, 2007; 179(4): 2105 - 2114.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. F. Yates, A. M. Paterson, K. F. Nolan, S. P. Cobbold, N. J. Saunders, H. Waldmann, and P. J. Fairchild
Induction of Regulatory T Cells and Dominant Tolerance by Dendritic Cells Incapable of Full Activation
J. Immunol., July 15, 2007; 179(2): 967 - 976.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. J. Callaghan, F. J. Rouhani, M. C. Negus, A. J. Curry, E. M. Bolton, J. A. Bradley, and G. J. Pettigrew
Abrogation of Antibody-Mediated Allograft Rejection by Regulatory CD4 T Cells with Indirect Allospecificity
J. Immunol., February 15, 2007; 178(4): 2221 - 2228.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
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]

Home page
 Int ImmunolHome page
J. A. Kapp, K. Honjo, L. M. Kapp, X. y. Xu, A. Cozier, and R. P. Bucy
TCR transgenic CD8+ T cells activated in the presence of TGF{beta} express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection
Int. Immunol., November 1, 2006; 18(11): 1549 - 1562.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. K. Asiedu, K. J. Goodwin, G. Balgansuren, S. M. Jenkins, S. Le Bas-Bernardet, U. Jargal, D. M. Neville Jr, and J. M. Thomas
Elevated T Regulatory Cells in Long-Term Stable Transplant Tolerance in Rhesus Macaques Induced by Anti-CD3 Immunotoxin and Deoxyspergualin
J. Immunol., December 15, 2005; 175(12): 8060 - 8068.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
O. B. Herrera, D. Golshayan, R. Tibbott, F. S. Ochoa, M. J. James, F. M. Marelli-Berg, and R. I. Lechler
A Novel Pathway of Alloantigen Presentation by Dendritic Cells
J. Immunol., October 15, 2004; 173(8): 4828 - 4837.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
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]

Home page
 BloodHome page
S. Vigouroux, E. Yvon, E. Biagi, and M. K. Brenner
Antigen-induced regulatory T cells
Blood, July 1, 2004; 104(1): 26 - 33.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 J. Immunol.Home page
T.-C. Chen, S. P. Cobbold, P. J. Fairchild, and H. Waldmann
Generation of Anergic and Regulatory T Cells following Prolonged Exposure to a Harmless Antigen
J. Immunol., May 15, 2004; 172(10): 5900 - 5907.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
V. Mirenda, I. Berton, J. Read, T. Cook, J. Smith, A. Dorling, and R. I. Lechler
Modified Dendritic Cells Coexpressing Self and Allogeneic Major Histocompatability Complex Molecules: An Efficient Way to Induce Indirect Pathway Regulation
J. Am. Soc. Nephrol., April 1, 2004; 15(4): 987 - 997.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
S. Jiang, N. Camara, G. Lombardi, and R. I. Lechler
Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo
Blood, September 15, 2003; 102(6): 2180 - 2186.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
Y. Zhai and J. W. Kupiec-Weglinski
Regulatory T Cells in Kidney Transplant Recipients: Active Players but to What Extent?
J. Am. Soc. Nephrol., June 1, 2003; 14(6): 1706 - 1708.
[Full Text] [PDF]

Home page
 J. Immunol.Home page
E. V. Fedoseyeva, K. Kishimoto, H. K. Rolls, B. M.-W. Illigens, V. M. Dong, A. Valujskikh, P. S. Heeger, M. H. Sayegh, and G. Benichou
Modulation of Tissue-Specific Immune Response to Cardiac Myosin Can Prolong Survival of Allogeneic Heart Transplants
J. Immunol., August 1, 2002; 169(3): 1168 - 1174.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. Graca, S. Thompson, C.-Y. Lin, E. Adams, S. P. Cobbold, and H. Waldmann
Both CD4+CD25+ and CD4+CD25- Regulatory Cells Mediate Dominant Transplantation Tolerance
J. Immunol., June 1, 2002; 168(11): 5558 - 5565.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Chiffoleau, G. Beriou, P. Dutartre, C. Usal, J.-P. Soulillou, and M. C. Cuturi
Role for Thymic and Splenic Regulatory CD4+ T Cells Induced by Donor Dendritic Cells in Allograft Tolerance by LF15-0195 Treatment
J. Immunol., May 15, 2002; 168(10): 5058 - 5069.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Yamada, A. Chandraker, T. M. Laufer, A. J. Gerth, M. H. Sayegh, and H. Auchincloss Jr.
Cutting Edge: Recipient MHC Class II Expression Is Required to Achieve Long-Term Survival of Murine Cardiac Allografts After Costimulatory Blockade
J. Immunol., November 15, 2001; 167(10): 5522 - 5526.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. Leon, R. Perez, A. Lage, and J. Carneiro
Three-Cell Interactions in T Cell-Mediated Suppression? A Mathematical Analysis of Its Quantitative Implications
J. Immunol., May 1, 2001; 166(9): 5356 - 5365.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wise, M. P.
Right arrow Articles by Waldmann, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wise, M. P.
Right arrow Articles by Waldmann, H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS