Shuiping Jiang

Imperial College London, London, ENG, United Kingdom

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Publications (18)83.86 Total impact

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    ABSTRACT: CD4(+)CD25(+) regulatory T cells (Tregs) play a crucial role in controlling immune responses. It is an appealing strategy to harness Tregs for adoptive cell therapy to induce tolerance to allografts. Several approaches have been developed to expand antigen-specific Tregs. Despite the large body of experimental data from murine studies demonstrating the great potential of these cells for clinical application, Treg adoptive transfer therapy was used in immunodeficient animals or in strain combinations with limited histiocompatibility. The aim of this study was to investigate whether Treg lines can protect from allograft rejection in a fully MHC-mismatched strain combination and whether the presence of Tregs with indirect allospecificity offered an advantage compared to self-reactive Tregs. Treg lines with self-specificity or with indirect allospecificity were generated by stimulating BL/6 CD4(+)CD25(+) T cells with autologous immature DCs either unpulsed or pulsed with K(d) peptide. The Treg lines were injected into recipient mice in combination with temporary depletion of CD8(+) T cells and a short course of Rapamycin. The data demonstrate that Treg lines with indirect allospecificity can be generated and most importantly they can induce indefinite survival of BALB/c hearts transplanted into BL/6 recipients when combined with short term immunosuppression. However, the Treg lines with self-specificity were only slightly less effective. The data presented in this study demonstrate the potential of ex vivo expanded Treg lines for adoptive cell therapy to promote transplantation tolerance.
    Transplant Immunology 06/2009; 21(4):203-9. · 1.52 Impact Factor
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    ABSTRACT: T cell responses to MHC-mismatched transplants can be mediated via direct recognition of allogeneic MHC molecules on the cells of the transplant or via recognition of allogeneic peptides presented on the surface of recipient APCs in recipient MHC molecules - a process known as indirect recognition. As CD4(+)CD25(+) Tregs play an important role in regulating alloresponses, we investigated whether mouse Tregs specific for allogeneic MHC molecules could be generated in vitro and could promote transplantation tolerance in immunocompetent recipient mice. Tregs able to directly recognize allogeneic MHC class II molecules (dTregs) were obtained by stimulating CD4(+)CD25(+) cells from C57BL/6 mice (H-2(b)) with allogeneic DCs from BALB/c mice (H-2(d)). To generate Tregs that indirectly recognized allogeneic MHC class II molecules, dTregs were retrovirally transduced with TCR genes conferring specificity for H-2K(d) presented by H-2A(b) MHC class II molecules. The dual direct and indirect allospecificity of the TCR-transduced Tregs was confirmed in vitro. In mice, TCR-transduced Tregs, but not dTregs, induced long-term survival of partially MHC-mismatched heart grafts when combined with short-term adjunctive immunosuppression. Further, although dTregs were only slightly less effective than TCR-transduced Tregs at inducing long-term survival of fully MHC-mismatched heart grafts, histologic analysis of long-surviving hearts demonstrated marked superiority of the TCR-transduced Tregs. Thus, Tregs specific for allogeneic MHC class II molecules are effective in promoting transplantation tolerance in mice, which suggests that such cells have clinical potential.
    Journal of Clinical Investigation 11/2008; 118(11):3619-28. · 12.81 Impact Factor
  • David S Game, Xuetao Cao, Shuiping Jiang
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    ABSTRACT: So profound is the potential for regulatory T cells (Tregs) to control unwanted immune responses that in 2008 an entire conference was dedicated to them. The underlying concept of this conference, "China Tregs 2008," was that unraveling the cellular biology of Tregs will lead to important advances for therapies in virtually all human disease processes and in transplantation. The master-switch of immune regulation is the forkhead transcription factor Foxp3; in mice, Foxp3 is a sine qua non for regulatory activity. At "China Tregs 2008," the cell signaling events leading to the expression of Foxp3 and those events downstream were explored together with presentations on how the latest knowledge of the biology of Tregs is being translated in the clinic.
    Science Signaling 02/2008; 1(51):mr3. · 7.65 Impact Factor
  • David S. Game, Robert I. Lechler, Shuiping Jiang
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    ABSTRACT: The pursuit of transplantation tolerance is still in progress some 53 years after Medawar and colleagues’ first description. It has been established beyond doubt that regulatory T cells can confer donor-specific tolerance in mouse models of transplantation. However, this is crucially dependent on the strain combination, the organ transplanted and most importantly, the ratio of Tregs to alloreactive effector T cells. The ex-vivo expansion of Tregs is one solution to increase the number of alloantigen specific cells capable of suppressing the alloresponse. This technique has been used to demonstrate long term graft survival in mouse models, where ex-vivo expanded, alloantigen specific T cells are shown to preferentially migrate to, and proliferate in, the graft and draining lymph node. When such models are selected to test the role of the different allorecognition pathways for Treg induced graft survival, it appears that only a modest direct pathway alloresponse is sufficient to abrogate tolerance in immunocompetent mice. This remains the case when Tregs are expanded with both direct and indirect pathway allospecificity. Therefore, in human transplantation it is likely that depletion of the majority of direct pathway alloreactive T cells will be required to tip the balance in favour of regulation. Ex-vivo expansion of alloantigen specific, indirect pathway human Tregs, which can cross regulate the residual direct pathway has been established. Rapid expansion of these cells is possible, while they retain antigen specificity, suppressive properties and favourable homing markers. Furthermore, considerable progress has been made in the last few years to define which immunosuppressive drugs favour the expansion and function of Tregs. It is proposed that a trial of Treg therapy in combination with depletion of alloreactive T cells and short term immunosuppression is on the near horizon for human transplantation.
    12/2007: pages 335-354;
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    ABSTRACT: CD4+CD25+ regulatory T (Treg) cells play a critical role in the induction and maintenance of peripheral immune tolerance. In experimental transplantation models in which tolerance was induced, donor-specific Treg cells could be identified that were capable of transferring the tolerant state to naive animals. Furthermore, these cells appeared to have indirect allospecificity for donor antigens. Here we show that in vivo alloresponses can be regulated by donor alloantigen-specific Treg cells selected and expanded in vitro. Using autologous dendritic cells pulsed with an allopeptide from H2-Kb, we generated and expanded T-cell lines from purified Treg cells of CBA mice (H2k). Compared with fresh Treg cells, the cell lines maintained their characteristic phenotype, suppressive function, and homing capacities in vivo. When cotransferred with naive CD4+CD25- effector T cells after thymectomy and T-cell depletion in CBA mice that received CBK (H2k+Kb) skin grafts, the expanded Treg cells preferentially accumulated in the graft-draining lymph nodes and within the graft while preventing CBK but not third-party B10.A (H2k+Dd) skin graft rejection. In wild-type CBA, these donor-specific Treg cells significantly delayed CBK skin graft rejection without any other immunosuppression. Taken together, these data suggest that in vitro-generated tailored Treg cells could be considered a therapeutic tool to promote donor-specific transplant tolerance.
    Blood 02/2007; 109(2):827-35. · 9.78 Impact Factor
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    ABSTRACT: Harnessing naturally arising CD4+ CD25+ regulatory T cells (Tregs) for potential adoptive cell therapy is hampered by their innate autoreactivity and their limited number. CD4+ CD25+ Tregs were purified from peripheral blood of human leukocyte antigen (HLA) DR1*0101+ A2- individuals, and stimulated with autologous monocyte-derived dendritic cells (DCs). Here we show that CD4+ CD25+ Tregs specific for an HLA A2 (103-120) peptide can be selected from the peripheral blood CD4+ CD25+ T cell population of a healthy individual and detected using a tetramer comprised of HLA DRB1*0101 and the A2 peptide. The selected cells can be expanded substantially (i.e., a 1600-fold increase over a two-week period) by T-cell receptor (TCR) stimulation and high-doses of interleukin-2 (IL-2). The CD4+ CD25+Tregs with indirect allospecificity for the A2 peptide showed more potent antigen-specific suppression than polyclonal CD4+ CD25+ Tregs. These data may pave the way for clinical studies using CD4+ CD25+ Tregs with indirect allospecificity as therapeutic reagents for the induction of donor-specific transplantation tolerance.
    Transplantation 01/2007; 82(12):1738-43. · 3.78 Impact Factor
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    ABSTRACT: The key goal in clinical transplantation is the induction of donor-specific transplantation tolerance to minimise the morbidity and mortality associated with long-term immunosuppression. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) expressing forkhead transcript factor FoxP3 play a crucial role in the prevention of autoimmunity, and appear to mediate transplantation tolerance, and these cells can have indirect allospecificity for donor antigens. Here we show that self-reactive human CD4(+)CD25(+) Tregs can be subverted into allopeptide-specific cells in vitro and be expanded to large cell numbers, and that similar in vitro expanded murine CD4(+)CD25(+) Tregs with indirect allospecificity were capable of inducing donor-specific experimental transplantation tolerance. These data provide a platform for clinical studies using CD4(+)CD25(+) Tregs with indirect allospecificity as potential reagents for the induction of donor-specific transplantation tolerance.
    International Immunopharmacology 01/2007; 6(13-14):1879-82. · 2.42 Impact Factor
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    ABSTRACT: Naturally arising CD4(+)CD25(+) regulatory T cells play a pivotal role in the prevention of autoimmunity and in the induction of donor-specific transplantation tolerance. Harnessing regulatory cells for potential adoptive cell therapy is hampered by their lack of antigen-specificity and their limited numbers. Here we describe the generation and expansion of murine CD4(+)CD25(+) T cells with antigen-specificity for an K(d) peptide as potential reagents for adoptive cell therapy in promoting donor-specific transplantation tolerance. Using bone marrow-derived autologous dendritic cells pulsed with the K(d) peptide, we generated T cell lines from purified CD4(+)CD25(+) T cells from C56BL/6 mice. The T cell lines expressed high level of CD25 and low level of CD45RB and CD69. They maintained the expression of CD62L, GITR, CTLA-4 and more importantly FoxP3. The CD4(+)CD25(+) T cell lines were anergic after TCR stimulation and produced little cytokine such as IL-2 and IFN-gamma. Importantly, they were more potent than freshly isolated CD4(+)CD25(+) T cells in suppressing proliferation and cytokine secretion by effector CD4(+) T cells. Furthermore, the CD4(+)CD25(+) T cell lines could be expanded to large cell numbers and maintained in culture up to 1 year. The K(d)-specific CD4(+)CD25(+) T cell lines will be invaluable in devising a strategy for the induction of cardiac transplantation tolerance in wild-type B6 mice carrying a full mismatch BALB/c heart.
    International Immunopharmacology 01/2007; 6(13-14):1883-8. · 2.42 Impact Factor
  • Shuiping Jiang
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    ABSTRACT: Despite the success of organ transplantation, most transplant patients are susceptible to variety of infections and cancer due to the use of potent immunosuppressive drugs for life to prevent transplant rejection. Regulatory T cells are capable of preventing transplant rejection while leaving the immune system's function against infection intact. Thus, adoptive cell therapy using patient-specific regulatory T cells as individualized medicine could promote clinical transplantation tolerance without the use of nonspecific immunosuppressive agents.
    Discovery medicine 01/2007; 6(36):239-42. · 2.97 Impact Factor
  • Shuiping Jiang, Robert I Lechler
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    ABSTRACT: Naturally occurring CD4+CD25+ regulatory T cells (Tregs) play a critical role in the control of periphery tolerance to self-antigens. Interestingly, they also control immune responses to allergens and transplant antigens. Recent studies in animal models have shown that adoptive transfer of CD4+CD25+ Tregs can prevent or even cure allergic and autoimmune diseases, and appear to induce transplantation tolerance. Thus, adoptive cell therapy using patient-specific CD4+CD25+ Tregs has been emerged as individualized medicine for the treatment of inflammatory disease including allergy, autoimmune disease and transplant rejection. Furthermore, strategies to activate and expand antigen-specific CD4+CD25+ Tregs in vivo using pharmacological agents may represent a novel avenue for drug development.
    Inflammation & Allergy - Drug Targets (Formerly ?Current Drug Targets - Inflammation & Allergy) 01/2007; 5(4):239-42.
  • Shuiping Jiang, Giovanna Lombardi
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    ABSTRACT: In the past years, research on immune regulation has exploded thanks to the re-emergence of T suppressor cells (Ts), now coined as regulatory T cells (Tregs). It has been established that different populations of Tregs exist in the immune system, and the generation, mechanism of suppression and the cellular and molecular targets of Tregs are being unraveled. This will lead to new opportunities for immune intervention to treat autoimmune disease and to achieve clinical transplantation tolerance. The scientific progress in the field of translational medicine was presented at the 7th International Conference on New Trends in Immunosuppression and Immunotherapy in Berlin in February 2006. In this special issue of International Immunopharmacology, several papers submitted to this congress will highlight some of the advances in this burgeoning field of translational medicine.
    International Immunopharmacology 01/2007; 6(13-14):1874-8. · 2.42 Impact Factor
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    ABSTRACT: In the past decade, several types of regulatory T cells (Tregs) have been identified to play a pivotal role in the control of autoimmunity and transplantation tolerance in rodents and in human beings, including innate regulatory NKT cells and gammadelta T cells, naturally occurring FoxP3 expressing CD4(+)CD25(+) T cells, and in-vitro induced Tregs including interleuking-10 (IL-10)-secreting Tr1 CD4(+) T cells, TGF-beta-producing Th3 CD4(+) T cells, anergic CD4(+) T cells, CD8(+)CD28(-) and CD3(+)CD4(-)CD8(-) T cells. Recent studies have shown that innate and adaptive Tregs may be linked and act in concert to mediate immunosuppression. As our understanding of regulatory T cell populations has substantially advanced, compelling evidence support the prospect that in-vitro expanded, patient-tailored Tregs with indirect anti-donor allospecificity could be potential reagents as adoptive cell therapy for individualized medicine to promote clinical transplantation tolerance.
    Human Immunology 11/2006; 67(10):765-76. · 2.30 Impact Factor
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    ABSTRACT: Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to play a key role in the control of autoimmunity. Interestingly, they are also capable of mediating transplantation tolerance and they can have indirect allospecificity for donor antigens. An increasing body of evidence in experimental studies has indicated that adoptive transfer of in vitro expanded CD4+CD25+ Tregs with indirect antidonor allospecificity can induce long-term donor-specific transplantation tolerance. Thus, adoptive cell therapy using patient-specific CD4+CD25+ Tregs as individualised medicine to promote clinical transplantation tolerance is promising.
    Expert opinion on biological therapy 11/2006; 6(10):1003-9. · 3.22 Impact Factor
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    ABSTRACT: Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) expressing forkhead transcript factor box P3 have been established as a key regulator for the control of autoimmunity. A growing body of experiments in animal models has provided compelling evidence that the adoptive transfer of CD4(+)CD25(+) Tregs can cure many autoimmune and allergic diseases, and appear to induce donor-specific transplantation tolerance. Thus, customer-tailored CD4(+)CD25(+) Tregs have emerged as potential reagents for adoptive cell therapy for individualized medicine. This review discusses recent advances towards that goal.
    Expert Review of Clinical Immunology 05/2006; 2(3):387-92. · 2.89 Impact Factor
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    ABSTRACT: CD4(+)CD25(+) and CD1d-restricted natural killer T (NKT) cells are thymus-derived self-reactive regulatory T cells that play a key role in the control of pathological immune responses. Little is known about functional cooperation between innate regulatory NKT cells and adaptive CD4(+)CD25(+) regulatory cells. Here we show that human CD4(+)Valpha24(+)Vbeta11(+) (CD4(+) NKT) cells isolated from peripheral blood by flow cytometric cell sorting secrete substantial amounts of IL-2 after stimulation with dendritic cells (DC) and alpha-Galactosylceramide. When cocultured with CD4(+)CD25(+) cells, CD4(+) NKT cells promoted moderate proliferation of CD4(+)CD25(+) cells. The proliferation of CD4(+)CD25(+) T cells was due to soluble IL-2 produced by activated CD4(+) NKT cells. The expanded CD4(+)CD25(+) cells remained anergic and retained their potent suppressive properties. These findings indicate that unlike conventional CD4(+) and CD8(+) T cells, which are susceptible to CD4(+)CD25(+) regulatory cell suppression, NKT cells promote CD4(+)CD25(+) regulatory cell proliferation. These data raise the possibility that NKT cells can function as helper cells to CD4(+)CD25(+) regulatory T cells, thereby providing a link between the two naturally occurring populations of regulatory T cells.
    European Journal of Immunology 05/2005; 35(4):1193-200. · 4.97 Impact Factor
  • Shuiping Jiang, Osquel Herrera, Robert I Lechler
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    ABSTRACT: It has long been appreciated that MHC alloantigens can be recognized via two pathways; direct and indirect. The relative contributions of these two pathways to transplant rejection are partially understood. In studies of transplantation tolerance it appears that regulatory T cells (Trs) with indirect allospecificity, particularly the CD4+CD25+ population, play a key role and can regulate responder cells with direct allospecificity for the same alloantigens. One of the conundrums that remains is how helper T and Tr cells with indirect allospecificity regulate T cells with direct allospecificity. At face value, this appears to break the rules of linkage that require interacting T cells to make contact with the same antigen-presenting cell. A third, 'semi-direct' pathway involving MHC exchange may help to resolve this conundrum. Insights into how these pathways interact in transplant immunity and tolerance will assist the pursuit of clinical tolerance.
    Current Opinion in Immunology 11/2004; 16(5):550-7. · 8.77 Impact Factor
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    ABSTRACT: Although CD4+CD25+ regulatory T cells are pivotal in the prevention of autoimmunity and appear to mediate transplantation tolerance, little is known concerning their antigen specificity. Here we describe the induction of a human CD4+CD25+ regulatory T-cell line specific for a defined peptide alloantigen (human leukocyte antigen A2 [HLA-A2] 138-170) by priming purified CD4+CD25+ cells ex vivo. The regulatory cells were anergic and retained their ability to suppress antigen-driven responses of CD4+CD25- cells. They inhibited not only interleukin 2 (IL-2) secretion by CD4+CD25- T cells specific for the same peptide but also direct alloresponse of naive CD4+CD25- T cells stimulated by semiallogeneic dendritic cells (DCs) in the presence of the peptide ("linked suppression"). They also suppressed the response of CD4+ T cells specific for viral and bacterial antigens. The suppressive T-cell line showed sustained high CD25 expression. These findings suggest that peripheral CD4+CD25+ regulatory cells are a precommitted cell lineage from which cells with specificity for non-self-peptides can be selected. This may pave the way for inducing and expanding peptide antigen-specific regulatory T cells ex vivo for cell therapy in transplantation, allergy, and autoimmune disease.
    Blood 10/2003; 102(6):2180-6. · 9.78 Impact Factor
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    Shuiping Jiang, Robert I Lechler
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    ABSTRACT: A role for immunoregulatory T cells in the maintenance of self-tolerance and in transplantation tolerance has long been suggested, but the identification of such cells has not been achieved until recently. With the characterisation of spontaneously occurring CD4+CD25+ and NK1.1+ T subpopulations of T cells as regulatory cells in rodents and in humans, together with several in vitro generated regulatory T-cell populations, it seems possible that 'customised' regulatory cells possessing antidonor specificity may become therapeutic tools in clinical transplantation tolerance.
    American Journal of Transplantation 06/2003; 3(5):516-24. · 6.19 Impact Factor

Publication Stats

664 Citations
83.86 Total Impact Points

Institutions

  • 2003–2008
    • Imperial College London
      • • Faculty of Medicine
      • • Section of Immunology
      London, ENG, United Kingdom
  • 2005–2007
    • King's College London
      Londinium, England, United Kingdom
  • 2006
    • King College
      Guymon, Oklahoma, United States