Skin-Specific Alloantigens in Miniature Swine1

Fuchimoto, Yasushi; Gleit, Zachary L.; Huang, Christene A.; Kitamura, Hiroshi; Schwarze, Margaret L.; Menard, Matthew T.; Mawulawde, Kwabena; Madsen, Joren C.; Sachs, David H.

doi:10.1097/00007890-200107150-00024

Cited by 41 publications

(35 citation statements)

References 14 publications

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“…To further test the possibility that mixed chimeras may have effective direct but not indirect tolerance to donor antigens, we created BALB/c plus CB6F1 into B6 mixed chimeras. In this way the population of recipient T cells in mixed chimeras that normally recognizes donor BALB/c antigens only via indirect presentation on recipient MHC, would also recognize these antigens presented directly [29] on the F1 donor cells. Even though BALB/c hematopoietic cell antigens could be presented directly in the context of both donor and recipient MHC, these chimeras also rejected BALB/c donor skin (Fig.…”

Section: Direct and Indirect Tolerance To Hematopoietic Cells But Notmentioning

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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Section: Direct and Indirect Tolerance To Hematopoietic Cells But Notmentioning

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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“…Using the approach of combined organ and bone marrow transplantation in hosts conditioned with nonmyeloablative regimens, tolerance has been achieved in rodents, monkeys, mini-swine, and, more recently, in humans (2-7). However, in some studies acceptance of the marrow transplants as judged by the development of mixed chimerism was associated with the rejection of skin grafts or heart grafts (5,8). Initial reports of radiation chimeras that rejected donor skin grafts suggested that skin-specific transplantation Ags explained the rejection, since the infusion of epidermal cells into chimeras resulted in skin graft acceptance (9,10).…”

Section: Immune Tolerance To Combined Organ and Bone Marrow Transplanmentioning

confidence: 99%

“…However, there is considerable variability of skin and s.c. myocardial graft acceptance in mixed chimeras depending upon the host-conditioning regimen that is used, the level of donor T cell chimerism achieved, and the time interval between transplantation of the donor bone marrow/hemopoietic progenitor cells and the organ graft (2,3,11,12). In some studies, there is uniform acceptance of these organ grafts (2,3,11) and in others the majority of the organ grafts are rejected despite high levels of chimerism (5,12).…”

Section: Immune Tolerance To Combined Organ and Bone Marrow Transplanmentioning

confidence: 99%

Immune Tolerance to Combined Organ and Bone Marrow Transplants After Fractionated Lymphoid Irradiation Involves Regulatory NK T Cells and Clonal Deletion

Higuchi

Zeng

Shizuru

et al. 2002

The Journal of Immunology

104

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Immune tolerance to organ transplants has been reported in laboratory animals and in humans after nonmyeloablative conditioning of the host and infusion of donor bone marrow cells. We examined the mechanisms of immune tolerance to mouse cardiac allografts in MHC-mismatched hosts that developed mixed chimerism after posttransplant conditioning with a 2-wk course of multiple doses of lymphoid tissue irradiation, depletive anti-T cell Abs, and an infusion of donor bone marrow cells. When CD1−/− or Jα281−/− hosts with markedly reduced NK T cells were used instead of wild-type hosts, then the conditioning regimen failed to induce tolerance to the heart allografts despite the development of mixed chimerism. Tolerance could be restored to the CD1−/− hosts by infusing enriched T cells from the bone marrow of wild-type mice containing CD1-reactive T cells but not from CD1−/− host-type mice. Tolerance could not be induced in either IL-4−/− or IL-10−/− hosts given the regimen despite the development of chimerism and clonal deletion of host T cells to donor MHC-Ags in the IL-10−/− hosts. We conclude that immune tolerance to bone marrow transplants involves clonal deletion, and tolerance to heart allografts in this model also involves regulatory CD1-reactive NK T cells.

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“…Rather, p21−/− recipients mounted an exaggerated Th1 response relative to WT mice which was associated with accelerated graft rejection (Table I) and exacerbated graft pathology (Figure 1). These differences in the in vitro and in vivo scenarios are likely reflected by the fact that there are clear microenvironmental differences present in vivo following transplantation with differential expression of antigens and compartmentalization of responses that may occur (18)(19)(20)(21)(22)(23)(24)(25). However, the in vivo correlate clearly contains the most relevance as this is most important clinically and reflects the net effect of all of the above variables.…”

Section: Discussionmentioning

confidence: 99%

“…It is generally accepted that immune responses initiated in vitro may not accurately reflect the complexity of responses initiated in vivo where compartmentalization, microenvironmental parameters, and tissue specific expression of antigens may impact outcome (18)(19)(20)(21)(22)(23)(24)(25). Therefore we assessed the ability of WT and p21−/− mice to mount proliferative and cytokine responses following cardiac transplantation.…”

Section: Impact Of P21 On In Vivo T Cell Responses Following Transplamentioning

confidence: 99%

Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

Welling

Csencsits

et al. 2008

Surgery

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Background-The cyclin-dependent kinase (cdk) inhibitor p21 inhibits cellular proliferation of many cell types, including T cells. However, autoimmune models have yielded conflicting results regarding the role of cdk inhibitors and T cell function. The role of p21 in T cell function following transplantation has not been directly investigated. We hypothesized that p21 plays an important role in alloantigen-driven responses in vitro in mixed lymphocyte cultures (MLC) and in vivo using the heterotopic murine cardiac allograft model.

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Skin-Specific Alloantigens in Miniature Swine1

Abstract: These findings support the concept that skin expresses immunogenic alloantigens that either are not expressed or are not immunogenic in cardiac or hematopoietic tissue.

Cited by 41 publications

References 14 publications

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

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

Immune Tolerance to Combined Organ and Bone Marrow Transplants After Fractionated Lymphoid Irradiation Involves Regulatory NK T Cells and Clonal Deletion

Regulation of alloimmune Th1 responses by the cyclin-dependent kinase inhibitor p21 following transplantation

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