Microchimerism and rejection in clinical transplantation

Elwood, Eric T.; Larsen, Christian; Maurer, David; Routenberg, Kristine L.; Neylan, John F.; Whelchel, John D.; O’Brien, David; Pearson, Thomas C.

doi:10.1016/s0140-6736(96)09105-2

Cited by 145 publications

(72 citation statements)

References 18 publications

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“…Because the number of amplifiable genomes was 500 to 3,000 cells as judged by amplifying a one-copy autosomal gene (data not shown), the microchimerism sensitivity detection limit was between 0.2% and 0.03%. In addition, analysis of female peripheral blood lymphocytes as well as of eight prepubertal females skin samples (nevi) and eight BCC from nongrafted females showed the absence of any Y signal, confirming the specificity of quantitative PCR which has been previously validated by others (19).…”

Section: Resultssupporting

confidence: 81%

“…Of note, because the study was done on archival specimens, we could not test the presence of donor cells within the recipient's peripheral blood lymphocytes. However, such findings are frequently described in kidney transplants, reaching levels up to 70% of cases in the literature (19,20). In accordance, in some skin specimens, there were some donor cells expressing CD45.…”

Section: Discussionmentioning

confidence: 98%

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Skin Carcinoma Arising From Donor Cells in a Kidney Transplant Recipient

et al. 2005

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The incidence of skin cancer is increased in transplant recipients. UV radiation, papillomaviruses, and immunosuppression participate in the pathogenesis of these tumors. In addition, donor cells may leave the grafted organ, reach peripheral tissues and either induce immune phenomena or possibly take part in tissue remodeling. Herein, we investigated the possible involvement of donor cells in the development of skin tumors in kidney allograft recipients. We analyzed a series of 48 malignant and benign cutaneous tumors developing in 14 females who had been grafted with a male kidney. The number of male cells was measured on microdissected material by quantitative PCR for Y chromosome. In the samples with high levels of male cells, fluorescent in situ hybridization (FISH) with X and Y probes and/or immuno-FISH with anticytokeratin antibodies were carried out. Male cells were detected in 5/15 squamous cell carcinomas and Bowen disease (range 4-180 copies), 3/5 basal cell carcinomas (91-645), 6/11 actinic keratosis (7-102), 2/4 keratoacanthoma (22-41), and 2/5 benign cutaneous lesions (14-55). In a basal cell carcinoma specimen with a high number of male cells, FISH showed that most cells within the tumoral buds were XY. In this lesion, immuno-FISH showed the presence of XY cytokeratin-positive cells indicating that the tumor nests contained male keratinocytes. In contrast, in other female transplants, male cells present in the tumors were not epithelial. In conclusion, stem cells originating from a grafted kidney may migrate to the skin, differentiate, or fuse as keratinocytes that could, rarely, undergo cancer transformation. (Cancer Res 2005; 65(5): 1755-60)

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Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 98%

Skin Carcinoma Arising From Donor Cells in a Kidney Transplant Recipient

et al. 2005

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“…Previous studies have demonstrated that early mixed chimerism may not always persist over the long term, particularly with regimens that involve a combination of immunosuppressive techniques [34,35]. Hence, tolerance in mixed chimerism must be more carefully assessed in the setting of transplantation, owing to the possibility that chimerism may be dissociated with tolerance [36][37][38]. The results of DN-Treg-mediated NK cell suppression was intriguing, prompting us to further study whether adoptive transfer of DN-Treg could promote engraftment of allogeneic BM cells.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, tolerance in mixed chimerism must be more carefully assessed in the setting of transplantation, owing to the possibility that chimerism may be dissociated with tolerance [36][37][38]. The results of DN-Treg-mediated NK cell suppression was intriguing, prompting us to further study whether adoptive transfer of DN-Treg could promote engraftment of allogeneic BM cells.…”

Section: Discussionmentioning

confidence: 99%

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

Wang

et al. 2007

Eur J Immunol

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Bone marrow (BM) transplantation is an efficient approach to develop donor-specific tolerance and prevent chronic rejection. Allogeneic BM transplantation is limited by donor T cell-mediated graft-versus-host disease, requirement of cytoreduction and high numbers of BM cells. In addition of these drawbacks, recent studies demonstrate that not only T cells, but also NK cells can mediate BM rejection, and long-term mixed chimerism depends on NK cell tolerance. Thus, NK cell is another potential barrier against engraftment of BM and an important target in efforts to induce transplant tolerance. We have previously identified a novel type of Treg with the phenotype TCRab + CD3 + CD4 -CD8 -(double-negative, DN). We and others have demonstrated that DN-Treg can effectively suppress anti-donor T cell responses. In this study, we found that donor-derived DN-Treg can suppress NK cell-mediated allogeneic BM graft rejection in both parent-to-F1 and fully MHC-mismatched BM transplantation models. Perforin and FasL in DN-Treg play important roles in the suppression of NK cells. Furthermore, adoptive transfer of DN-Treg can promote a stable mixed chimerism and donor-specific tolerance without inducing graft-versus-host disease. These results demonstrate a potential approach to control innate immune responses and promote allogeneic BM engraftment. IntroductionEstablishing donor-specific transplant tolerance is beneficial for several reasons: it can prevent chronic rejection and avoid side effects related to long-term immunosuppressive drug treatment. It also can help patients to preserve their own natural immunity against infections and tumors. Achieving mixed chimerism via BM transplantation is an efficient approach that directs the immune system to regard the donor as 'self'. By generating specific immunologic tolerance to donor transplants, chronic rejection as well as the need for ongoing immunosuppression can be avoided [1][2][3].Rejection of MHC-mismatched allografts is largely mediated by a recipient's CD4 + and CD8 + T cells. Recent studies, however, have demonstrated that NK cells are another potential barrier in allograft rejection and tolerance [4][5][6][7]. Furthermore, studies have shown that NK cells can mediate BM rejection [8,9]. This notion has been well addressed in the hybrid resistance model, in which parental BM cells, not solid organs, are vigorously rejected by an F1 hybrid [10,11]. This rejection is mediated solely by a recipient's NK cells, not by T cells, NKT cells or B cells [12][13][14] [20,21].In recent studies, we found that TCRab + CD3 + CD4 -CD8 -(double-negative, DN) T cells possess immuneregulatory functions and play an important role in the development of tolerance post-transplantation [22][23][24][25]. We have demonstrated that mouse DN-Treg specifically can eliminate activated syngeneic anti-donor CD4 + T cells, CD8 + T cells, and B cells [22,23,25,26]. Furthermore, adoptive transfer of DN-Treg leads to significant prolongation of donor-specific skin and heart allografts in a single MHC-mis...

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“…Two types of chimerism can be acquired through kidney transplantation: an induced chimerism in combined kidney and bone marrow transplantation to generate immune tolerance in the recipient 1 Many studies have tried to correlate the persistence of circulating donor cells with clinical outcome of recipients, 5-7 but very few have considered the presence of foreign DNA/cells either in the recipient blood or allograft prior to transplantation. 8 For the first time, in a recent study we provided evidence that women with end stage renal disease (ESRD) carry male microchimerism (Mc) in peripheral blood mononuclear cells before kidney transplantation. 9 When compared with healthy women, the presence of male Mc was more frequent (62% vs. 16%) and at higher levels [98 vs. 0.…”

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confidence: 99%