Porcine CTLA4-Ig Lacks a MYPPPY Motif, Binds Inefficiently to Human B7 and Specifically Suppresses Human CD4+ T Cell Responses Costimulated by Pig But Not Human B7

Vaughan, Andrew N.; Malde, Prupti; Rogers, Nicola J.; Jackson, Ian; Lechler, Robert I.; Dorling, Anthony

doi:10.4049/jimmunol.165.6.3175

Cited by 46 publications

(37 citation statements)

References 32 publications

(25 reference statements)

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“…Cell preparation, reagents, and antibodies. The human M1 fibroblast cells (M1.DR1) transfected with porcine CD80 (M1pB7.1) or CD86 (M1pB7.2), CHO cells expressing murine CD80 (CHOmB7.1) or CD86 (CHOmB7.2), and the immortalized porcine endothelial cell line F6 have been previously described (18,20,21). The lipofectamine-based method for generating transfected clones based on the immortalized porcine EC "C29" has been previously described (22), as have the eukaryotic expression vectors containing constructs encoding cDNA for SLA-DRc A and B genes (23).…”

Section: Methodsmentioning

confidence: 99%

“…pCTLA4-Ig was purified as previously described (18). Murine CTLA4/Fc chimera (mCTLA-Ig) and human IgG1 control antibodies were purchased from R&D Systems and the Binding Site (Birmingham, U.K.), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…With this goal in mind, we recently acquired two sets of promising data. In one study, we generated a porcine CTLA4-Ig (pCTLA4-Ig) fusion protein and compared it with the human CTLA4-Ig (hCTLA4-Ig) in functional assays (18). In response to porcine xenogeneic stimulator cells, hCTLA4-Ig and pCTLA4-Ig were comparably effective at inhibiting human CD4 ϩ T-cell proliferation.…”

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confidence: 99%

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Achieving Permanent Survival of Islet Xenografts by Independent Manipulation of Direct and Indirect T-Cell Responses

et al. 2005

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Recent success in pancreatic islet allotransplantation has raised expectations but has equally highlighted the acute shortage of donor tissue. The use of xenogeneic tissue would help to address this shortage; however, strong cellular immunity limits the application of this approach. T-cell responses to xenogeneic tissues involve recognition of intact species-mismatched major histocompatibility complex (MHC) molecules, the direct pathway, and xenogeneic proteins presented as peptides by responder-type MHC molecules, the indirect pathway. In this study, we exploited the species difference to selectively and sequentially inhibit direct and indirect xenoresponses after transplantation of porcine islets into mice. Selective inhibition of the direct response was achieved using porcine CTLA4-Ig, which binds preferentially to pig versus mouse B7 molecules. Selective inhibition of the indirect response was achieved using murine CTLA4-Ig, which binds preferentially to mouse B7 molecules. Administration of porcine CTLA4-Ig alone caused modest prolongation of islet survival. Injection of murine CTLA4-Ig alone had a minimal effect. However, the injection of the porcine fusion protein early and the murine homolog late after grafting led to permanent survival of the porcine islets, in the absence of any other immunosuppression. These results suggest that a similar approach could have clinical utility in porcine islet xenotransplantation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Achieving Permanent Survival of Islet Xenografts by Independent Manipulation of Direct and Indirect T-Cell Responses

et al. 2005

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“…Phenotyping was performed with the following monoclonal antibodies: anti-SWC3 porcine panmyeloid cell marker (74-22-15) (44), anti-major histocompatibility complex class I (MHC-I; 74-11-10) (40) and II (MHC-II; MSA3) (19), anti-CD14 (MIL2) (50), anti-CD16 (G7) (17), and anti-CD25 (231.3B2; Serotec, Oxford, United Kingdom). CD80/86 was detected by using the hCTLA4-mouse immunoglobulin fusion protein (Alexis) (51), and PCV2 antigen was detected by using an anti-PCV2 capsid protein (open reading frame 2 [ORF2]) monoclonal antibody. Briefly, cells were incubated with the antibodies, and reactivity was detected by using fluorescein isothiocyanate (FITC)-, phycoerythrin-, or biotin-conjugated goat F(abЈ) 2 anti-mouse isotypespecific immunoglobulins (Southern Technology, Birmingham, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Dendritic Cells Harbor Infectious Porcine CircovirusType 2 in the Absence of Apparent Cell Modulation or Replication of theVirus

Vincent¹,

Carrasco²,

Herrmann³

et al. 2003

J Virol

105

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Dendritic cells (DCs) play crucial roles in innate and adaptive immune responses, rendering them critical targets for virus infections. Porcine circovirus type 2 (PCV2) is associated with the development of postweaning multisystemic wasting syndrome (PMWS) in piglets. We demonstrate here that 80 to 90% of monocyte-derived and bone marrow-derived DCs interact with PCV2 similar to the early stages of an infection. There was no evidence for virus replication, but the virus did persist in DCs without loss of infectivity nor the induction of cell death. This could reflect an abortive infection, but there was no evidence of virus uncoating-the infectivity remained intact for at least 5 days. Alternatively, the results may reflect DC endocytosis of antigenic material. However, there was no modulation of DC surface major histocompatibility complex class I and class II, CD80/86, CD25, CD16, or CD14. Furthermore, infected DC did not transmit virus to syngeneic T lymphocytes, even when the latter were activated. Such coculture did not induce PCV2 replication or death of the lymphocytes or DCs. These results demonstrate that PCV2 can persist in DCs in the absence of virus replication or degradation. Such a silent virus infection presents a novel mechanism of not only immune evasion but also escaping the DC degradation pathway. Because of their migratory capacity, infection of DCs thus provides a potent vehicle for transport of the virus throughout the host without the need for replication. In addition, the lymphopenia seen in PMWS is not a direct effect of the virus on lymphocytes but would require additional events, as proposed by others.

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“…15 However, the ability of mixed chimerism to induce human T-cell tolerance to porcine xenografts has yet to be explored because of the lack of a suitable model system. It has been unclear whether or not genetic incompatibilities in immune cytokines, 16,17 accessory molecules, [17][18][19] and other unknown molecules between the 2 species might impede the induction of human T-cell tolerance to porcine xenografts through mixed chimerism. To address these questions, we have developed a murine model that permits the induction of both sustained porcine hematopoietic chimerism and active human thymopoiesis.…”

Section: Introductionmentioning

confidence: 99%

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Lan

Wang

Diouf

et al. 2004

Blood

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Xenotransplantation from pigs could provide a potential solution to the severe shortage of allogeneic donor organs. Because xenogeneic tissues are subject to vigorous immune rejection, tolerance induction is likely to be essential to the success of clinical xenotransplantation. Here we explore the possibility of inducing human T-cell tolerance to porcine xenografts through mixed chimerism. We previously showed that NOD/SCID-Tg mice expressing porcine cytokine transgenes permit the induction of durable porcine hematopoietic chimerism. In this study we achieved human T-cell development in these mice by engrafting human fetal thymus/liver tissues. In porcine hematopoietic chimeras, human thymus grafts were populated with porcine class II high cells in addition to human cells, and human T cells were tolerant of the porcine hematopoietic donor as measured by mixed lymphocyte reaction assay and skin grafting. This study proves the principle that porcine chimerism induces tolerance of xenoreactive human T cells. IntroductionThe severe shortage of allogeneic organ donors currently limits the number of transplantations performed. 1,2 This supply-demand disparity could be corrected by the ability to use organs from other species (xenografts). In view of the ethical issues and impracticalities associated with the use of nonhuman primates, interest has focused on other species, in particular the pig, as the most suitable organ donor species for humans. In addition to organ size and physiologic similarities to humans, the ability to rapidly breed and inbreed pigs makes them particularly amenable to genetic modifications that could improve their ability to function as organ donors to humans. [3][4][5][6][7] However, organ transplantations across discordant species barriers are subject to vigorous immunologic rejection. 1,8 One might, therefore, expect the amount of nonspecific immunosuppression that would be required to overcome xenograft rejection to be so great that recipients would succumb to infections. Thus, it would be highly desirable to eliminate the immune response to xenografts through the induction of tolerance.Mixed chimerism has been proven to be a powerful and reliable approach for tolerance induction across allogeneic and closely related xenogeneic barriers. 9-14 Our recent studies showed that this approach also induces tolerance in a pig-to-mouse, highly disparate xenogeneic combination. 15 However, the ability of mixed chimerism to induce human T-cell tolerance to porcine xenografts has yet to be explored because of the lack of a suitable model system. It has been unclear whether or not genetic incompatibilities in immune cytokines, 16,17 accessory molecules, [17][18][19] and other unknown molecules between the 2 species might impede the induction of human T-cell tolerance to porcine xenografts through mixed chimerism. To address these questions, we have developed a murine model that permits the induction of both sustained porcine hematopoietic chimerism and active human thymopoiesis. Our results demonstrate...

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Porcine CTLA4-Ig Lacks a MYPPPY Motif, Binds Inefficiently to Human B7 and Specifically Suppresses Human CD4+ T Cell Responses Costimulated by Pig But Not Human B7

Cited by 46 publications

References 32 publications

Achieving Permanent Survival of Islet Xenografts by Independent Manipulation of Direct and Indirect T-Cell Responses

Achieving Permanent Survival of Islet Xenografts by Independent Manipulation of Direct and Indirect T-Cell Responses

Dendritic Cells Harbor Infectious Porcine CircovirusType 2 in the Absence of Apparent Cell Modulation or Replication of theVirus

Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

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