Induction of Permanent Mixed Chimerism and Skin Allograft Tolerance Across Fully MHC-Mismatched Barriers by the Additional Myelosuppressive Treatments in Mice Primed with Allogeneic Spleen Cells Followed by Cyclophosphamide

Tomita, Yukihiro; Yoshikawa, Masahide; Zhang, Qiwei; Shimizu, Ichiro; Okano, Shinji; Iwai, Toshiro; Yasui, Hirofumi; Nomoto, Kikuo

doi:10.4049/jimmunol.165.1.34

Cited by 40 publications

(58 citation statements)

References 43 publications

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“…Skin grafts were prepared and transplanted as previously described by Ref. 35 Briefly, full-thickness tail skin (0.8 Â 0.8 cm) was grafted onto the lateral flank of recipient mice. A suture was sewn onto each corner of the graft and subsequently bandaged.…”

Section: Discussionmentioning

confidence: 99%

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

et al. 2007

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CD4 þ CD25 þ regulatory T cells (Treg) are potent immunosuppressive cells active in controlling normal pathological immune responses. The mechanisms of this suppression have been investigated under various conditions. In this report, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)/death receptor 5 (DR5) was explored as one of the pivotal factors for the suppression and cytotoxicity induced by CD4 þ CD25 þ Treg. Cell death was involved in the suppression induced by activated CD4 þ CD25 þ Treg in vitro. The induction of CD4 þ T cell death was not mediated by the CD95/CD95L pathway, but rather depended upon the upregulation of TRAIL in the Treg. Blocking the TRAIL/DR5 pathway resulted in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg in vitro. Activated Treg displayed TRAIL-dependent cytotoxicity against CD4 þ T cells in vivo. The prolonged survival of allogeneic skin grafts induced by Treg was inhibited by DR5-blocking antibodies. Our findings suggest that the TRAIL/DR5 pathway is one of the mechanisms used by Treg to regulate immune responses both in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

et al. 2007

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“…One could surmise that researchers in the field have a pre-determined bias (full tolerance is the preferred outcome clinically), as evidenced by the numerous studies that chose to use clinically irrelevant MHC-congenic donors (minor antigen-matched) that are likely to give a false impression of full tolerance (skin acceptance) [16,[38][39][40][41][42][43][44], including in protocols very similar to our own [45]. No explanation is given in such studies for the unusual choice of donor/recipient combination.…”

Section: Discussionmentioning

confidence: 99%

“…While split tolerance has been observed in some mixed chimerism strategies [7, 13], many current studies are specifically designed to avoid the issue by using donor and recipient combinations matched for minor histocompatibility antigens [14][15][16][17][18]. The prevention of split tolerance by minor antigen matching could result from a number of mechanisms, including reduced indirect reactivity to the donor or elimination of allelic tissuespecific antigens.…”

Section: Introductionmentioning

confidence: 99%

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Luo¹,

Chan²,

Shapiro³

et al. 2007

Eur J Immunol

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Stable mixed chimerism has been considered the most robust tolerance strategy. However, rejection of solid donor tissues by chimeras has been observed, a state termed split tolerance. Since new non-myeloablative mixed chimerism approaches are being actively pursued, we sought to determine whether they lead to full tolerance or split tolerance and to define the mechanisms involved. Fully mismatched mixed chimeras generated by induction with various lymphocyte-depleting antibodies along with either low-dose irradiation or busulfan and temporary sirolimus, maintained stable mixed chimerism but nevertheless rejected donor skin grafts. Generation of stable mixed chimerism using antibody targeting CD40L, but not depleting antibodies to CD4 and CD8, could prevent split tolerance when skin grafts were given together with donor bone marrow. Minor antigen matching abrogated the ability of effector T cells to reject donor skin grafts. A CFSE killing assay indicated that chimeras were both directly and indirectly tolerant of donor hematopoietic cell antigens, suggesting that minor mismatches triggered a tissue-specific response. Thus, split tolerance due to tissuerestricted polymorphic antigens prevents full tolerance in a number of nonmyeloablative mixed chimerism protocols and a 'tolerizing' agent is required to overcome split tolerance. A model of the requirements for split tolerance is presented.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/36938_s.pdf IntroductionMuch of the effort to develop donor-specific transplantation tolerance has been focused on inducing peripheral tolerance through costimulation blockade. While initially promising, with more extensive tests of this approach the success has been somewhat limited, particularly when translated to larger animal models and to the clinic [1]. In hindsight this may not be surprising given that tolerance naturally occurs primarily in the thymus and only secondarily in the periphery [2]. In contrast, the approach of generating hematopoietic chimerism via bone marrow transplantation (BMT) takes advantage of the thymic central tolerance mechanisms, and is considered the most robust method of inducing donor-specific tolerance [3][4][5][6]. The chimer- ism approach is limited clinically by the harsh recipient conditioning needed to establish chimerism and the possibility of graft-vs.-host disease [7]. More recently less toxic strategies have been developed that establish mixed allogeneic chimerism, where substantial levels of donor and recipient hematopoietic cells co-exist in the recipient, and have raised hope that robust transplantation tolerance will soon be routine clinically [6]. Mixed chimerism has been considered to induce tolerance to all other donor tissues. If true, mixed chimerism could be a solution for both solid organ transplantation and cellular transplants, such as allogeneic islets used to treat type-1 diabetes. However, studies in full chimeras, where virtually all hematopoietic cells in the recipien...

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“…injection of 1 Â 10 8 allogeneic spleen cells (SC) (day 0) followed, 2 days later, by an i.p. administration of 200 mg/kg of CP in mice [7][8][9][10]. By using the H-2-matched murine combination of AKR into C3H and MoAbs against the T-cell markers (Thy1.1 and Thy1.2) and Mls-a reactive TCR Vb6, we have demonstrated the concurrent mechanisms of CP-induced tolerance.…”

Section: Introductionmentioning

confidence: 99%

“…These mechanisms are: (i) clonal destruction of antigenstimulated and then proliferating T cells by CP [8,9], (ii) establishment of stable mixed chimerism [11], (iii) intrathymic clonal deletion [8,9] and (iv) and regulatory mechanisms at the late stage of tolerance [12]. Recently, we have developed a modified method that includes additional myelosuppressive treatments and induces both permanent mixed chimerism and skin allograft tolerance in H-2 mismatched combinations [10].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Limitations of Cyclophosphamide‐induced Tolerance against αGal Antigen

Shimizu¹,

Tomita²,

Iwai³

et al. 2005

Scand J Immunol

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In the present study, we have elucidated the efficacy of two cyclophosphamide (CP)-induced tolerance protocols for the induction of B-cell tolerance against Gala1-3Galb1-4GlcNAc (aGal) antigens. a1,3-galactosyltransferase-deficient (GalT -/-; H-2 b/d ) mice received with 1 Â 10 8 AKR (aGal þ/þ H-2 k ) spleen cells (SC) followed by 200 mg/kg CP, or alternatively followed by 200 mg/kg CP, 30 mg/kg Busulfan (BU) and 1 Â 10 8 T-cell-depleted AKR bone marrow cells (BMC). The generation of both anti-aGal and anti-donor antibodies were completely suppressed, but normal antibody production against third party antigens was observed after BALB/c skin grafting in both groups of GalT -/-mice. In GalT -/-mice, treated with SC and CP, mixed chimerism was not observed. Cellular rejection was observed in grafted donor AKR hearts with an absence of humoral rejection, whereas humoral rejection was observed in untreated GalT -/-mice. On the other hand, long-term mixed chimerism and permanent acceptance of donor AKR skin graft and heart graft were achieved in GalT -/-mice treated with SC, CP, BU and BMC. These results demonstrate the efficacy of classical drug-induced tolerance in the induction of B-cell tolerance against aGal antigens. However, induction of stable mixed chimerism was required for the suppression of cellular rejection.

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Induction of Permanent Mixed Chimerism and Skin Allograft Tolerance Across Fully MHC-Mismatched Barriers by the Additional Myelosuppressive Treatments in Mice Primed with Allogeneic Spleen Cells Followed by Cyclophosphamide

Cited by 40 publications

References 43 publications

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Efficacy and Limitations of Cyclophosphamide‐induced Tolerance against αGal Antigen

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