The effect of macrophage depletion on delayed xenograft rejection: studies in the guinea pig‐to‐C6‐deficient rat heart transplantation model

Wu, Guosheng; Korsgren, Olle; Rooijen, Nico van; Wennberg, Lars; Tibell, Annika

doi:10.1034/j.1399-3089.1999.00031.x

Cited by 24 publications

(13 citation statements)

References 26 publications

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“…Thus, the development of strategies for specifically suppressing xenogeneic cell-triggered macrophage activation may be essential to the maintenance of durably functional cellular xenografts, and may also be beneficial in solid organ xenotransplantation for which macrophages have also been implicated in rejection. 23,24 SIRP␣ is an ITIM-bearing inhibitory receptor expressed on macrophages that plays an important role in controlling macrophage activation. 12,13 It has been demonstrated that SIRP␣ on macrophages recognizes CD47 as a marker of "self" and that CD47-SIRP␣ signaling prevents autologous phagocytosis of normal cells.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

Wang

VerHalen

Madariaga

et al. 2006

Blood

113

109

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IntroductionThe severe shortage of allogeneic donors currently limits the number of organ transplantations performed. 1 This supplydemand 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, pigs are considered 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. 2,3 However, xenotransplantation from pigs is hampered by vigorous immunologic rejection. In addition to the adaptive immune responses, which play critical roles in both allograft and xenograft rejection, the innate immune system also mediates strong rejection of organs and cells from discordant xenogeneic donors.Studies in various models have shown that macrophages contribute significantly to xenograft rejection. In xenotransplant recipients, macrophages are activated and recruited rapidly, and their responses to xenoantigens precede the activation of T cells. 4 It has been reported that macrophages contribute significantly to the rejection of porcine hematopoietic cells 5,6 and islet xenografts 7-9 in both rodents and primates. Similarly, macrophages also mediate strong rejection of human hematopoietic cells 10 and islets 11 in mice. The rapid and refractory rejection of xenogeneic hematopoietic cells by macrophages greatly impedes the application of mixed chimerism, a means of tolerance induction, to xenotransplantation.Macrophage activation is regulated by the balance between activating and inhibitory signals. CD47 (integrin-associated protein), a member of the Ig superfamily, is ubiquitously expressed in all tissues and serves as a ligand for signal regulatory protein ␣ (SIRP␣; also known as CD172a, SHPS-1), an immune inhibitory receptor on macrophages. 12,13 Studies using CD47-deficient mice demonstrated that SIRP␣ on macrophages recognizes CD47 as a marker of "self." 14 CD47-SIRP␣ signaling prevents phagocytosis of normal hematopoietic cells by autologous macrophages 14,15 and reduces the sensitivity of antibody-and complement-opsonized cells to phagocytosis. 16,17 These results indicate that macrophages rely on CD47 expression to distinguish "self " from "nonself " and to set a threshold for macrophage-mediated phagocytosis of opsonized cells. Thus, donor cells would be highly susceptible to phagocytosis by recipient macrophages in a xenogeneic transplantation setting if donor CD47 fails to interact with recipient SIRP␣. As a first step in investigating this question, in this study we assessed the role of CD47 in phagocytosis of xenogeneic cells in the setting of pig-to-mouse xenotransplantation. Our results indicate that the failure of pig CD47 to interact with mouse SIRP␣ makes porcine cells highly sensitive to phagocytosis by mouse macrophages. Furthermore, genetic manipulati...

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Section: Discussionmentioning

confidence: 99%

Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

Wang

VerHalen

Madariaga

et al. 2006

Blood

113

109

View full text Add to dashboard Cite

show abstract

“…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%

“…The problem with these studies is that the evidence supporting the important role for macrophages was indirect. Temporary depletion of macrophages in nonobese diabetic (NOD) mice and diabetic C57BL/6 mice by liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2 MDP) caused a delay in xenograft rejection as well as a marked delay in the cellular infiltration by macrophages and T cells (12,18), supporting a major role for macrophages in xenograft rejection. However, the characteristics of this important macrophage-mediated response remain unclear.…”

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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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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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“…Only little is known about the mechanism and immunosuppressive require- Complement C6-deficient PVG (C-) recipients, unable to construct the terminal MAC (C5b-429) of the complement cascade due to an isolated genetic deficiency in C6 [42], reject discordant GP cardiac xenografts in an accelerated acute fashion within 1-2 days [3, 13, 21,22,44,45]. The C6 deficiency blocks a late step in complement activation of the classic and alternative complement pathway.…”

Section: Discussionmentioning

confidence: 99%

Busulfan depletes neutrophils and delays accelerated acute rejection of discordant xenografts in the guinea pig-to-rat model

et al. 2003

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Complement factor plays a critical role in mediating hyperacute rejection of discordant xenografts. In order to explore the mechanism of discordant xenograft rejection, we investigated kinetics and phenotypes of the cellular infiltrate in xenografts in untreated and leukocyte‐depleted recipients, in relation to graft survivial. Guinea pig cardiac xenografts were heterotopically transplanted to totally C6‐deficient PGV (C‐) rats. Grafts were removed after 0, 6, 12, and 24 h (n= 6). Histological evaluation was performed with hematoxylin and eosin (H & E) and immunoperoxidase staining. The agents fucoidin and busulfan were applied to delay xenograft rejection further. Within 6 h, minimal perjection further. Within 6 h, minimal perivascular edema with isolated infiltrating CD11b/c‐ and ED1‐positive cells were found. An intense infiltration of CD11b/c‐ and EDI‐positive cells with intestitial hemorrhage was present after 24 h, though with little CD161 and CD3 cell infiltration. Inhibition of cell adhesion by fucoidin did not prolong xenograft survival (34 ± 15 h, n= 4, P <0.47), but the depletion of granuloecytes by injection of busulfan did prolong survival of the discordant xenograts, to 62±22 h (n 7, P ± 0.0039). These reults demonstrate a significant effect of specific depletion of granulocytes and macrophages by busulfan therapy on guinea pig cardiac xenograft survival in PVG (C‐) rats, suggesting the participation of these infiltrating cells in the xenoreractive rejection process.

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The effect of macrophage depletion on delayed xenograft rejection: studies in the guinea pig‐to‐C6‐deficient rat heart transplantation model

Cited by 24 publications

References 26 publications

Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

Attenuation of phagocytosis of xenogeneic cells by manipulating CD47

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

Busulfan depletes neutrophils and delays accelerated acute rejection of discordant xenografts in the guinea pig-to-rat model

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