T cell‐mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival

Dorling, Anthony; Lechler, Robert I.

doi:10.1111/j.1399-3089.1998.tb00034.x

Cited by 65 publications

(41 citation statements)

References 117 publications

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“…The lack of preformed Abs and the failure of human NK cells to reconstitute the host enable the study of cell-mediated xenoresponses in the absence of hyperacute or acute vascular rejection. It is generally predicted that human anti-porcine T cell xenoresponses will be greater than alloresponses (3,4). The finding that pig skin xenografts are not rejected by human PBMC in SCID/ beige mice (17), in contrast to the marked infiltration and destruction of allografts in the same model (18 -21), is unexpected.…”

Section: Discussionmentioning

confidence: 42%

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Human TNF Can Induce Nonspecific Inflammatory and Human Immune-Mediated Microvascular Injury of Pig Skin Xenografts in Immunodeficient Mouse Hosts

Kirkiles-Smith¹,

Tereb²,

Kim³

et al. 2000

The Journal of Immunology

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TNF activates endothelial cells to express cell surface molecules that are necessary to recruit a local infiltrate of leukocytes. Because the actions of this proinflammatory cytokine are not species restricted, we investigated whether human TNF can up-regulate porcine endothelial adhesion molecules to elicit human T cell infiltration and damage of pig skin xenografts in a chimeric immunodeficient mouse model. We have previously demonstrated the vigorous rejection of human skin allografts and the absence of injury to porcine skin xenografts in human PBMC-SCID/beige mice. Intradermal administration of human TNF at high doses (600 or 2000 ng) caused nonspecific inflammatory damage of pig skin grafts, whereas low concentrations of TNF (60 or 200 ng) resulted in human PBMC-dependent injury of porcine endothelial cells. There was a strong correlation among pig skin xenograft damage, human T cell infiltration, and the TNF-induced up-regulation of swine MHC class I and class II molecules, VCAM-1, and, in particular, the de novo expression of porcine E-selectin. The microvascular damage and leukocytic infiltration elicited by TNF were enhanced by porcine IFN-γ, suggesting that xenografts may be less prone to cytokine-mediated injury due to the species-restricted effects of recipient IFN-γ. Our results indicate that maintenance of a quiescent endothelium, which does not express E-selectin or other activation-dependent adhesion molecules, is important in preventing human anti-porcine T cell xenoresponses in vivo and that TNF signaling molecules and TNF-responsive gene products are appropriate therapeutic targets to protect against human T cell-mediated rejection of pig xenografts.

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Section: Discussionmentioning

confidence: 42%

“…Based on in vitro studies, it has been predicted that human anti-porcine cellular xenoresponses will be considerably greater than alloresponses (3,4). Human T cells directly recognize swine MHC class I and II molecules, resulting in more vigorous proliferative responses compared with allogeneic stimuli (5-7).…”

mentioning

confidence: 99%

Human TNF Can Induce Nonspecific Inflammatory and Human Immune-Mediated Microvascular Injury of Pig Skin Xenografts in Immunodeficient Mouse Hosts

Kirkiles-Smith¹,

Tereb²,

Kim³

et al. 2000

The Journal of Immunology

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“…This is because mouse T-cells from a variety of inbred strains fail to mount primary in vitro responses to xenogeneic stimulators due to cross-species molecular incompatibilities that serve to limit the efficiency of direct xenorecognition (32). Even in those studies where a primary response to xenogeneic islets has been documented in vitro, it has often been shown to be dependent on the presence of recipient APCs, implying either a reliance on transcostimulation or an indirect presentation of processed xenoantigens (33).…”

Section: Discussionmentioning

confidence: 99%

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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“…However, the immunosuppressive protocols currently employed to prevent rejection of human allografts are clearly inadequate at preventing porcine xenograft rejection: a greater degree of immunosuppression is required, and this is thought to be due to the vigorous anti-pig-specific human T cell response (31,32). Consequently, safer alternative protocols for suppressing host T cell responses will be needed if clinical xenotransplantation is to match the success of clinical allotransplantation.…”

Section: Discussionmentioning

confidence: 99%

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

Malde

Rogers

et al. 2000

The Journal of Immunology

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The CTLA4 receptor (CD152) on activated T lymphocytes binds B7 molecules (CD80 and CD86) on APC and delivers a signal that inhibits T cell proliferation. Several regions involved in binding to B7 are known, but the relative importance of these is not clear. We have cloned porcine CTLA4 (pCTLA4). Although highly homologous to human CTLA4 (hCTLA4), the predicted protein sequence contains a leucine for methionine substitution at position 97 in the MYPPPY sequence. A fusion protein constructed from the extracellular regions of pCTLA4 and the constant regions of human IgG1 (pCTLA4-Ig) bound porcine CD86 with equivalent affinity to that of hCTLA4-Ig. However, pCTLA4-Ig bound poorly to human CD80 and CD86 expressed on transfectants and EBV-transformed human B cells. In functional assays with MHC class II-expressing porcine endothelial cells and human B cells, pCTLA4-Ig blocked human CD4+ T cell responses to pig but not human cells, whereas control hCTLA4-Ig inhibited responses to both. Comparison between mouse, human, and porcine CTLA4-Ig suggests that the selective binding of pCTLA4-Ig to porcine CD86 molecules is due to the L for M substitution at position 97. Our results indicate that pCTLA4-Ig may be a useful reagent to define the precise nature of the interaction between B7 and CTLA4. By failing to inhibit the delivery of costimulatory signals provided by human B7, it may also prove to be a relatively specific inhibitor of the direct human T cell response to immunogenic pig tissue.

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T cell‐mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival

Cited by 65 publications

References 117 publications

Human TNF Can Induce Nonspecific Inflammatory and Human Immune-Mediated Microvascular Injury of Pig Skin Xenografts in Immunodeficient Mouse Hosts

Human TNF Can Induce Nonspecific Inflammatory and Human Immune-Mediated Microvascular Injury of Pig Skin Xenografts in Immunodeficient Mouse Hosts

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

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

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