T Cells in Islet-Like Cell Cluster Xenograft Rejection

Benda, Birgitta; Sandberg, J; Holstad, Maria; Korsgren, Olle

doi:10.1097/00007890-199808270-00004

Cited by 23 publications

(30 citation statements)

References 27 publications

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“…Conventional wisdom has suggested that T cells are recruited to the graft via secondary lymphoid organs. Once they have reached the graft, they provide the signals necessary for ongoing macrophage recruitment (26). However, in our model, an alternative mechanism for macrophage involvement has been proposed.…”

Section: Discussionmentioning

confidence: 90%

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

100

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Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role in this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution with CD4+ T cells from BALB/c mice. Twelve days after CD4+ T cell reconstitution, purified macrophages (depleted of T cells) were isolated from CD4+ T cell-reconstituted FPP recipient mice and adoptively transferred to their nonreconstituted counterparts. After adoptive macrophage transfer, FPP recipient mice transferred with macrophages from CD4+ T cell-reconstituted mice demonstrated xenograft destruction along with massive macrophage infiltration at day 4 and complete graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients that received macrophages from nonreconstituted mice showed intact FPP xenografts with few infiltrating macrophages at both days 4 and 8 after macrophage transfer. The graft-infiltrating macrophages showed increased expression of their activation markers. Depletion of endogenous macrophages or any remaining CD4+ T cells did not delay graft rejection in the macrophage-transferred FPP recipients, whereas depletion of transferred macrophages with clodronate liposomes prevented graft rejection. Our results show that macrophages primed by FPP and activated by CD4+ T cells were attracted from the peripheral circulation and were capable of specific targeting and destruction of FPP xenografts. This suggests that in xenograft rejection, there are macrophage-specific recognition and targeting signals that are independent of those received by T cells.

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Section: Discussionmentioning

confidence: 90%

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

100

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“…Nevertheless, recent data obtained in our laboratory have shown that animals in which major parts of the TH1-associated cytokine pathway, namely interferon-? and IL-2 [38] or tumor necrosis factor-a [3], have been blocked, readily reject fetal porcine ICC xenografts. Taken together, it might be speculated that the rejection process of an ICC xenograft induces a vast immune response consisting of both TH1-and TH2-related components.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 in islet xenograft rejection

Benda

Korsgren

2001

Transplant International

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Earlier work on primate cardiac xenotransplantation has demonstrated a correlation between interleukin (1L)-6 levels and severity of vascular rejection. IL-6 was originally identified as a lymphokine inducing final maturation of B lymphocytes into antibody-secreting cells. The present study aimed to evaluate the role of IL-6 in fetal porcine islet-like cell cluster (ICC) xenograft rejection. Moreover, other authors have reported that eosinophils dominate the cellular response following discordant islet xenograft transplantation. Here, a technique for specific detection of eosinophils was applied. IL-6-deficient mice and wild-type controls were implanted with fetal porcine ICCs under the kidney capsule and killed 4-, 7-, and 10 days after transplantation. Xenografts were histologically evaluated, and serum samples were analyzed for IgM and IgG antibodies against ICC membrane antigens. IL-6-deficient mice and wild-type controls readily rejected the xenograft. On day 7 after transplantation, abundant numbers of F4/ 80' and Mac-l+ cells were found distributed throughout the collapsing graft accompanied by small amounts of eosinophils and peripherally accumulated CD3' T cells (predominantly CD4'). Significantly lower serum levels of IgM and IgG antibodies against ICC membrane antigens were observed in IL-6-deficient mice on day 4 or 7 after transplantation when compared to wild-type controls. No significant differences were seen on day 10 after transplantation. In both experimental groups, specific IgM and IgG antibody levels remained stable over time. In the pig-to-mouse model, IL-6 seems to be of minor importance to fetal porcine ICC xenograft rejection. Macrophages, and not eosinophils, dominate the cellular response associated with this process.

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“…1 and Tables 1-3. Fetal porcine ICCs were transplanted under the kidney capsule as previously described (17). One week to Ͼ1 year before transfer, recipient athymic (nu/nu) mice received an implant of either 3 l of fetal porcine ICC alone (Tables 1 and 3) IH, immunohistochemistry.…”

Section: Methodsmentioning

confidence: 99%

“…X0902; Dako A/S, Glostrup, Denmark) for 10 min. Immunohistochemical stainings using rat anti-mouse monoclonal antibodies to F4/80, Mac-1, MHC class II, CD3, CD8 (Serotec, Kidlington, U.K.), and CD4 (Pharmingen, San Diego, CA) were performed as previously described (17). The slides were counterstained with hematoxylin and mounted in glycerine gelatin.…”

Section: Methodsmentioning

confidence: 99%

A New Murine Model of Islet Xenograft Rejection

et al. 2003

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A new murine model of porcine islet-like cell cluster (ICC) xenograft rejection, avoiding interference of unspecific inflammation, was introduced and used to investigate rejection mechanisms. Athymic (nu/nu) mice were transplanted with syngeneic, allogeneic, or xenogeneic islets under the kidney capsule. After the original transplantation, immune cells in porcine ICC xenografts undergoing rejection in native immunocompetent mice were transferred to the peritoneal cavity of the athymic mice. At defined time points after transfer, the primary grafts were evaluated by immunohistochemistry and real-time quantitative RT-PCR to estimate cytokine and chemokine mRNA expression. Transfer of immunocompetent cells enabled athymic (nu/nu) mice to reject a previously tolerated ICC xenograft only when donor and recipient were matched for major histocompatibility complex (MHC). In contrast, allogeneic and syngeneic islets were not rejected. The ICC xenograft rejection was mediated by transferred T-cells. The main effector cells, macrophages, were shown to be part of a specific immune response. By day 4 after transplantation, there was an upreglation of both Th1-and Th2-associated cytokine transcripts. The transferred T-cells were xenospecific and required MHC compatibility to induce rejection. Interaction between the TCR of transferred T-cells and MHC on host endothelial cells and/or macrophages seems necessary for inducing ICC xenograft rejection.

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T Cells in Islet-Like Cell Cluster Xenograft Rejection

Cited by 23 publications

References 27 publications

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts

Interleukin-6 in islet xenograft rejection

A New Murine Model of Islet Xenograft Rejection

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