The strength of cell‐mediated xenograft rejection in the mouse is due to the CD4+ indirect response

Chitilian, Hovig V.; Laufer, Terri M.; Stenger, Karla; Shea, Susan; Auchincloss, Hugh

doi:10.1111/j.1399-3089.1998.tb00014.x

Cited by 48 publications

(40 citation statements)

References 16 publications

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“…Previous studies have shown this to be a strong immune response that is difficult to suppress (5,(32)(33)(34). It is different mechanistically from allograft rejection in that CD8 ϩ T cells are not involved, and more macrophage-mediated destruction occurs at early time points (35,36).…”

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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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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“…Despite the controversy over the existence of the direct pathway in mCD28Ig to pCD86 indicated the potential for porcine cells to costimulate mouse T cells directly, which was the pig-to-mouse xenotransplant setting (failure of mouse purified T cells to respond to PAEC), a direct T-cell BALB/c recipients displayed a predominant Th2 response with high IgG1 titers. Moreover, pCD86 blockresponse was demonstrated in a pig-to-mouse (II-4 + mouse) skin graft model (3). The contribution of donor ade by hCD152-hCD59 expression was accompanied by a marked reduction in anti-PAEC IgG1 production at CD80 to the xenogeneic direct response was shown after transplanting human pancreatic islets in mice using an 2 weeks posttransplantation.…”

mentioning

confidence: 98%

CD86 Blockade in Genetically Modified Porcine Cells Delays Xenograft Rejection by Inhibiting T-Cell and NK-Cell Activation

et al. 2004

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Porcine xenografts transplanted into primates are rejected in spite of immunosuppression. Identification of the triggering mechanisms and the strategies to overcome them is crucial to achieve long-term graft survival. We hypothesized that porcine CD86 (pCD86) contributes to xenograft rejection by direct activation of host T cells and NK cells. Formerly, we designed the human chimeric molecule hCD152-hCD59 to block pCD86 in cis. To test the efficacy in vivo, we have utilized a pig-to-mouse xenotransplant model. First, we showed that hCD152-hCD59 expression prevents the binding of murine CD28Ig to pCD86 on porcine aortic endothelial cells (PAEC) and dramatically reduces IL-2 secretion by Con A-stimulated mouse splenocytes in coculture. Moreover, IFN-γ secretion by IL-12-stimulated mouse NK cells was averted after coculture with hCD152-hCD59 PAEC. In vivo, control PAEC implanted under the kidney capsule were rapidly rejected (2-4 weeks) in BALB/c and BALB/c SCID mice. Rejection of hCD152-hCD59 PAEC was significantly delayed in both cases. Signs of immune modulation in the hCD152-hCD59-PAEC BALB/c recipients were identified such as early hyporesponsiveness and diminished antibody response. Thus, simply modifying the donor xenogeneic cell can diminish both T cell and NK cell immune responses. We specifically demonstrate that pCD86 contributes to rejection of porcine xenografts.

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“…Porcine insulin differs from human insulin by only cells do not respond to xenoantigens directly, but recogone amino acid (2). Furthermore, porcine islets can nornize host class II MHC/xenopeptide complexes via the malize blood glucose when implanted into diabetic aniindirect pathway of antigen presentation (1,13). mals (4,21).…”

Section: Introductionmentioning

confidence: 99%

Proliferative and Cytokine Responses in CTLA4-Ig-Treated Diabetic NOD Mice Transplanted with Microencapsulated Neonatal Porcine ICCs

2002

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Our goal is to develop effective islet xenografts for treating human diabetes. We have studied microencapsulated neonatal porcine islet cell clusters (ICCs) transplanted intraperitoneally in spontaneously diabetic NOD mice, where they function to maintain normoglycemia in the autoimmune host. Nonencapsulated neonatal porcine ICCs functioned for 4.5 ± 0.5 days before being rejected; encapsulation prolonged graft function to 17 ± 2 days. CTLA4-Ig treatment did not enhance the survival of nonencapsulated ICCs. However, CTLA4-Ig treatment significantly extended the function of encapsulated ICCs to 73 ± 5 days. Histological analyses demonstrated a profuse pericapsular cellular reaction associated with rejection of encapsulated islet xenografts in untreated mice, while this reaction was significantly reduced in CTLA4-Ig-treated mice. To study mechanisms of xenograft rejection in this model, we analyzed proliferative responses to neonatal porcine ICCs and cytokines present in the peritoneal cavities of transplanted mice. Spleen cells from both CTLA4-Igtreated and untreated rejecting NODs exhibited vigorous proliferation in the absence of antigenic stimulation, suggesting prior activation in vivo, while splenocytes from CTLA4-Ig-treated NODs with functioning grafts had low proliferative levels, equal to controls. Islet-specific proliferation was not detected in islet-rejecting mice, perhaps due to their high background levels. With the exception of elevated IL-6 levels, empty capsules did not provoke a significant peritoneal cytokine response compared with sham surgery or untransplanted control mice. However, IL-5, IL-12, TGF-β, and IL-1β were significantly elevated in NODs receiving encapsulated neonatal porcine ICCs compared with untransplanted controls. There were no significant differences between peritoneal cytokine concentrations in CTLA4-Ig-treated mice with long-term functioning grafts compared to mice that rejected grafts at earlier time points. We conclude that the combination of donor islet microencapsulation and brief treatment of the recipient with co-stimulatory blockade delays sensitization of the host, possibly by altering mechanism(s) for recruitment and/or activation of host effector cells.

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The strength of cell‐mediated xenograft rejection in the mouse is due to the CD4+ indirect response

Cited by 48 publications

References 16 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

CD86 Blockade in Genetically Modified Porcine Cells Delays Xenograft Rejection by Inhibiting T-Cell and NK-Cell Activation

Proliferative and Cytokine Responses in CTLA4-Ig-Treated Diabetic NOD Mice Transplanted with Microencapsulated Neonatal Porcine ICCs

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