The Main Infiltrating Cell in Xenograft Rejection Is a Cd4+ Macrophage and Not a T Lymphocyte

Wallgren, AnnaCarin; Karlsson‐Parra, Alex; Korsgren, Olle

doi:10.1097/00007890-199509270-00013

Cited by 141 publications

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“…This result raises interesting questions about the amount of shed antigens and the time of shedding required to develop an immune reaction on the microcapsules, as well as the possibility of a later accommodation of the immune system to the presence of the encapsulated xenogeneic islets. It has been shown that a strong immune reaction to the nonencapsulated fetal porcine islet cell clusters occurs during the first week of transplantation (24). In addition to the cellular infiltrate, we observed IgG deposition on the NPCCs contained in the microcapsules at 6 and 20 weeks after transplantation (Fig.…”

Section: Discussionmentioning

confidence: 58%

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

et al. 2003

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Differentiation and maturation of porcine neonatal pancreatic cell clusters (NPCCs) microencapsulated in barium alginate were assessed after transplantation into immunocompetent mice. Microencapsulated NPCCs were transplanted into the peritoneal cavity of streptozocin-induced diabetic B6AF1 mice (n ‫؍‬ 32). The microcapsules were removed at 2, 6, and 20 weeks and examined for cellular overgrowth, insulin content, and insulin secretory responses to glucose and glucose with theophylline. The differentiation, maturation, and proliferation of the ␤-cells in the NPCCs were assessed by immunohistochemistry. Blood glucose levels were normalized in 81% of the animals that received a transplant and remained normal until termination of the experiments at 20 weeks. Hyperglycemic blood glucose levels after explantation of the capsules confirmed the function of the encapsulated NPCCs. Insulin content of the encapsulated NPCCs was increased 10-fold at 20 weeks after transplantation compared with pretransplantation levels. A 3.2-fold increase of the ratio of the ␤-cell area to the total cellular area was observed at 20 weeks, demonstrating the maturation of NPCCs into ␤-cells. A s a result of recent progress (1), there is increased interest in islet transplantation as a potential therapy for type 1 diabetes. However, two major barriers must be overcome before islet transplantation can be provided for more patients: 1) the limited availability of human pancreatic tissue and 2) the need for permanent immunosuppression to prevent graft rejection and autoimmunity (2). Xenogeneic islets from pigs and cows (3-5) have been considered as potential sources of islets for transplantation. Many factors favor the use of pigs: the similar structure of porcine and human insulin, the comparable glucose levels, and that both pigs and humans are omnivores. Islet cells can be isolated in large numbers from adult (6 -9) or neonatal pigs (10,11). However, adult pig islets have proved to be difficult to isolate and tend to fare poorly in tissue culture, which has limited their use. Neonatal pancreatic cell clusters (NPCCs) contain a high proportion of islet precursor cells, can be maintained in culture, and differentiate into ␤-cells after transplantation (11). Naked (10,12) or microencapsulated NPCCs (13) have been shown to restore normoglycemia after transplantation into streptozotocin (STZ)-diabetic nude mice.The concept of a bioartificial pancreas, consisting of islets enclosed within immunobarrier membranes, provides a potential way to overcome the need for immunosuppression. Our group recently developed a promising encapsulation method that uses highly purified alginate cross-linked with BaCl 2 , without a separate permselective barrier, which protects islets against allorejection and autoimmunity (14). The aims of this study were to assess the protective capacity of simple barium-alginate capsules in a xenotransplantation model of NPCCs transplanted into STZ-induced diabetic immunocompetent mice and then to evaluate the growth, maturation, a...

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Section: Discussionmentioning

confidence: 58%

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

et al. 2003

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“…Macrophages have been proposed as one of the major effector cells responsible for CD4 ϩ T cell-mediated xenograft destruction. Unlike allografts in which the predominant cells seen are T cells, in rejecting xenografts the predominant cell is the macrophage (18,(23)(24)(25). The preponderance of macrophages in rejecting xenografts has led us and others to propose that these cells are primarily responsible for graft destruction (11)(12)(13)17).…”

Section: Discussionmentioning

confidence: 99%

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

Hawthorne

Lehnert

et al. 2003

The Journal of Immunology

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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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“…Instead, the CD4 ϩ T-cells recruit massive numbers of monocytes/macrophages to the site of the graft. The macrophages are activated and function as effector cells in the rejection (12,13).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, in these studies, the mice were reconstituted with naive lymphocytes dependent on antigen presentation and activation in the recipient mice at the time of transplantation, making the animal immunocompetent to all antigens, included in the CD4 ϩ or CD8 ϩ repertoire. However, the main effector cells during rejection in ICC to rodent xenotransplantation are activated macrophages (12)(13)(14), and depletion of macrophages has been shown to delay islet xenograft rejection in mice (13,15). In the present work, a novel experimental transfer model is introduced.…”

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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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The Main Infiltrating Cell in Xenograft Rejection Is a Cd4+ Macrophage and Not a T Lymphocyte

Cited by 141 publications

References 0 publications

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

Survival and Maturation of Microencapsulated Porcine Neonatal Pancreatic Cell Clusters Transplanted into Immunocompetent Diabetic Mice

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

A New Murine Model of Islet Xenograft Rejection

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