Spleen Plays an Important Role in Maintaining Tolerance After Removal of the Vascularized Heart Graft

Chosa, Eiichi; Hara, Masaki; Watanabe, Akira; Matsuzaki, Yasunori; Nakamura, Kunihide; Hamano, Kimikazu; Wood, Kathryn J.; Onitsuka, Toshio

doi:10.1097/01.tp.0000259928.16003.aa

Cited by 13 publications

(7 citation statements)

References 55 publications

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“…Continuous Ag exposure, such as an allograft, renders Ag-specific T cell unresponsiveness [52]. A previous study showed that post-transplantation tolerance was abrogated upon removal of a functioning allograft, suggesting that continuous Ag exposure is important to maintain the tolerant states [53].In contrast, a recent study demonstrated that maintenance of T cell tolerance is not necessarily restored by removing the tolerizing environment via transfer of tolerant T cells into another mouse without tolerogens [51]. Here, hu-PBMC-NSG mice suggested that a donor organ may not be associated with the mechanism of donor Ag hyporesponsiveness maintenance in T cells from off IS recipients.…”

Section: Discussionmentioning

confidence: 99%

Novel immunological approach to asses donor reactivity of transplant recipients using a humanized mouse model

et al. 2020

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In organ transplantation, a reproducible and robust immune-monitoring assay has not been established to determine individually tailored immunosuppressants (IS). We applied humanized mice reconstituted with human (hu-) peripheral blood mononuclear cells (PBMCs) obtained from living donor liver transplant recipients to evaluate their immune status. Engraftment of 2.5 × 10 6 hu-PBMCs from healthy volunteers and recipients in the NSG mice was achieved successfully. The reconstituted lymphocytes consisted mainly of hu-CD3 + lymphocytes with predominant CD45RA -CD62L lo TEM and CCR6 -CXCR3 + CD4 + Th1 cells in hu-PBMC-NSG mice. Interestingly, T cell allo-reactivity of hu-PBMC-NSG mice was amplified significantly compared with that of freshly isolated PBMCs (p<0.05). Furthermore, magnified hu-T cell responses to donor antigens (Ag) were observed in 2/10 immunosuppressed recipients with multiple acute rejection (AR) experiences, suggesting that the immunological assay in hu-PBMC-NSG mice revealed hidden risks of allograft rejection by IS. Furthermore, donor Ag-specific hyporesponsiveness was maintained in recipients who had been completely weaned off IS (n=4), despite homeostatic proliferation of hu-T cells in the hu-PBMC-NSG mice. The immunological assay in humanized mice provides a new tool to assess recipient immunity in the absence of IS and explore the underlying mechanisms to maintaining operational tolerance.

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Section: Discussionmentioning

confidence: 99%

Novel immunological approach to asses donor reactivity of transplant recipients using a humanized mouse model

et al. 2020

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“…In our patient, splenectomy was performed a few months prior to BMT. Splenectomy, essentially used in the context of humoral rejection prevention, has also been shown to promote tolerance induction in animal studies, through induction and amplification of T cells with regulatory and suppressor activity (13). Nevertheless, in the patient presented, the occurrence of a severe, post‐BMT, GVHD after splenectomy tends to suggest that splenectomy did not significantly contribute, in this setting, to tolerance induction.…”

Section: Discussionmentioning

confidence: 99%

Living related liver transplant following bone marrow transplantation from same donor: Long‐term survival without immunosuppression

Granot¹,

Loewenthal²,

Jakobovich³

et al. 2010

Pediatric Transplantation

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We report long-term (seven yr) immunological tolerance in a 16-yr-old boy, to a liver allograft donated by his father following a bone marrow transplant at age 2.5 yr from the same donor. The bone marrow transplant was complicated by severe GVHD leading to liver failure and the ensuing need for a liver transplant, performed under planned avoidance of immunosuppression. At one wk post-transplant, although a liver biopsy was histologically compatible with acute rejection, favorable clinical and biochemical evolution precluded initiating immunosuppressive therapy, thus highlighting the need for caution when interpreting early histological changes so that administration of unnecessary immunosuppression can be avoided. Induction of tolerance in transplant recipients remains an elusive goal. In those patients who had received conventional bone marrow transplants and had endured the consequences of GVHD, development of macrochimerism may allow immunosuppression-free solid organ transplantation from the same donor.

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“…The rejection of skin allografts depends on the presence of LN, whereas the rejection of vascularized heart allografts occurs in the presence of either the spleen or LN (Lakkis et al, 2000). On the contrary, Chosa et al (2007) showed that the spleen plays an important role in maintaining tolerance after removal of the vascularized heart graft. The APC migration route might explain the difference between models.…”

Section: Secondary Lymphoid Organsmentioning

confidence: 99%

“…In vascularized transplantation models, passenger leukocytes, including DC, are thought to migrate from the vascularized graft into the recipient spleen, where they activate T cells and cause rejection (Larsen et al, 1990a,b; Saiki et al, 2001). In the case of tolerance maintenance, naïve DC migrate to a tolerant graft and become regulatory or immature DC, these DC may then migrate to the spleen where they generate Treg (Chosa et al, 2007). CD4 + T cells from spleen of unresponsive cardiac allograft transplant recipients showed increased IL-10 and decreased IL-4 and IFNγ (DePaz et al, 2003).…”

Section: Secondary Lymphoid Organsmentioning

confidence: 99%

Tolerance and Lymphoid Organ Structure and Function

et al. 2011

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This issue of Frontiers in Immunologic Tolerance explores barriers to tolerance from a variety of views of cells, molecules, and processes of the immune system. Our laboratory has spent over a decade focused on the migration of the cells of the immune system, and dissecting the signals that determine how and where effector and suppressive regulatory T cells traffic from one site to another in order to reject or protect allografts. These studies have led us to a greater appreciation of the anatomic structure of the immune system, and the realization that the path taken by lymphocytes during the course of the immune response to implanted organs determines the final outcome. In particular, the structures, microanatomic domains, and the cells and molecules that lymphocytes encounter during their transit through blood, tissues, lymphatics, and secondary lymphoid organs are powerful determinants for whether tolerance is achieved. Thus, the understanding of complex cellular and molecular processes of tolerance will not come from “96-well plate immunology,” but from an integrated understanding of the temporal and spatial changes that occur during the response to the allograft. The study of the precise positioning and movement of cells in lymphoid organs has been difficult since it is hard to visualize cells within their three-dimensional setting; instead techniques have tended to be dominated by two-dimensional renderings, although advanced confocal and two-photon systems are changing this view. It is difficult to precisely modify key molecules and events in lymphoid organs, so that existing knockouts, transgenics, inhibitors, and activators have global and pleiotropic effects, rather than precise anatomically restricted influences. Lastly, there are no well-defined postal codes or tracking systems for leukocytes, so that while we can usually track cells from point A to point B, it is exponentially more difficult or even impossible to track them to point C and beyond. We believe this represents one of the fundamental barriers to understanding the immune system and devising therapeutic approaches that take into account anatomy and structure as major controlling principles of tolerance.

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Spleen Plays an Important Role in Maintaining Tolerance After Removal of the Vascularized Heart Graft

Abstract: The spleen is important in maintaining CD4CD25 regulatory T cells after primary allograft removal.

Cited by 13 publications

References 55 publications

Novel immunological approach to asses donor reactivity of transplant recipients using a humanized mouse model

Novel immunological approach to asses donor reactivity of transplant recipients using a humanized mouse model

Living related liver transplant following bone marrow transplantation from same donor: Long‐term survival without immunosuppression

Tolerance and Lymphoid Organ Structure and Function

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