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Thymic Rejuvenation and the Induction of Tolerance by Adult Thymic Grafts

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Thymic Rejuvenation and the Induction of Tolerance by Adult Thymic Grafts Thymic rejuvenation and the induction of tolerance by adult thymic grafts Shuji Nobori, Akira Shimizu, Masayoshi Okumi, Emma Samelson-Jones, Adam Griesemer, Atsushi Hirakata, David H. Sachs, and Kazuhiko Yamada* Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129 Edited by Ralph M. Steinman, The Rockefeller University, New York, NY, and approved October 25, 2006 (received for review June 22, 2006) The thymus, the site of origin of T cell immunity, shapes the repertoire procedure and then facilitated the induction of tolerance, suggest- of T cell reactivity through positive selection of developing T cells and ing that thymic function is largely controlled by the host environ- prevents autoimmunity through negative selection of autoreactive T ment rather than by the local thymic milieu. cells. Previous studies have demonstrated an important role for the thymus not only in central deletional tolerance, but also in the Results induction of peripheral tolerance by vascularized renal allografts in Thymic Involution with Age In Miniature Swine. We first examined juvenile miniature swine recipients. The same protocol did not induce the natural course of thymic involution with aging in naive minia- tolerance in thymectomized recipients nor in recipients beyond the ture swine (9). Right cervical thymic lobes were biopsied from 53 age of thymic involution. We subsequently reported that vascularized naive Massachusetts General Hospital (MGH) miniature swine of thymic lobe grafts from juvenile donors were capable of inducing different ages. The cortex and medulla in whole biopsy specimens tolerance in thymectomized juvenile hosts. However, the important containing at least 10 lobules were subjected to morphometric question remained whether aged, involuted thymus could also in- analysis by using NIH Image (Scion Image) software (10). duce tolerance if transplanted into thymectomized hosts, which, if Fig. 1A shows a plot of the ratio of cortical to medullary areas true, would imply that thymic involution is not an intrinsic property (c/m ratio) as a function of age in miniature swine. Fig. 1 B and C of thymic tissue but is rather determined by host factors extrinsic to shows representative histologic findings of naive thymic tissue at 4 the thymus. We report here that aged, involuted thymus transplanted months and 20 months of age, respectively. As shown in this figure, as a vascularized graft into juvenile recipients leads to rejuvenation of thymi from 4-month-old miniature swine had well defined, thick both thymic structure and function, suggesting that factors extrinsic cortical thymic areas, whereas thymi from 20-month-old animals to the thymus are capable of restoring juvenile thymic function to were consistently involuted. At 4 months of age, at which point aged recipients. We show furthermore that rejuvenated aged thymus peripheral tolerance can readily be induced (11), pigs had a c/m has the ability to induce transplant tolerance across class I MHC ratio between 3 and 5, whereas pigs older than 20 months, when barriers. These findings indicate that it may be possible to manipulate such peripheral tolerance could no longer be induced (12), had c/m thymic function in adults to induce transplantation tolerance after the ratios of Ϸ0.8 (Fig. 1A). The correlation coefficient between c/m age of thymic involution. ratio and age (Ϫ0.82) was highly significant (P Ͻ 0.0004). No difference was seen between the thymi of female and male animals. aging ͉ miniature swine ͉ thymus Rejuvenation of Aged Thymus Grafts in Juvenile Recipients. We next he thymus plays a central role in the development of immuno- assessed the ability of involuted thymus grafts to rejuvenate and to Tlogic tolerance. Thymic epithelial cells and dendritic cells in the support thymopoiesis after transplantation into juvenile animals. thymus are responsible for the induction of central tolerance to self VTL grafts were harvested from aged pigs (20–21 months of age) among developing T cells through negative selection. A similar and transplanted into MHC-matched, 4-month-old juvenile ani- process has been shown to lead to the development of central mals (recipients 1–3) that had been thymectomized 3 weeks earlier. transplantation tolerance to alloantigens after allogeneic hemato- A 28-day course of FK506 (tacrolimus) was administered to assure poietic stem cell (HSC) transplantation, because of negative selec- that the grafts would not be rejected because of minor antigen tion by HSC-derived donor dendritic cells that migrate to the host differences. FK506 has been found previously not to have measur- thymus (1–4). Finally, the thymus has been shown to be required able effects on thymus structure or involution in miniature swine for the rapid induction of the stable peripheral tolerance that occurs (13). The morphometric analysis of aged thymus grafts transplanted under the influence of a short course of calcineurin inhibitors after into juvenile recipients revealed marked rejuvenation of these allogeneic renal transplantation in miniature swine (5). grafts within two months of transplantation (Fig. 2). Aged thymic Ϯ Ϯ Thymic structure and function decline with age, however, leading grafts with an initial c/m ratio of 1 0.3 showed c/m ratios of 3.1 MEDICAL SCIENCES by adolescence to a significant reduction in thymic mass and an 0.8 by 60 days after transplant and 4.1 Ϯ 0.5 by 100 days after impaired ability to regenerate normal T cell numbers after T cell transplant. After day 180, the thymic architecture began to rein- depletion (6, 7). It is not clear whether this thymic involution is an intrinsic property of thymic tissue or is due to the effects of factors extrinsic to the thymus. Likewise, it remains unclear which Author contributions: K.Y. designed research; S.N., A.S., and K.Y. performed research; S.N., M.O., E.S.-J., A.G., A.H., D.H.S., and K.Y. analyzed data; and K.Y. wrote the paper. tolerance-inducing properties of the thymus are affected by its involution. The authors declare no conflict of interest. We have recently established a procedure for vascularized thymic This article is a PNAS direct submission. transplantation in MHC inbred miniature swine that permits a Abbreviations: CML, cell-mediated lympholysis; CTL, cytotoxic T lymphocyte; CyA, cyclo- sporine A; DP, double positive; FK506, tacrolimus; MLR, mixed lymphocyte response; PAA, transplanted thymus to function immediately after revasculariza- porcine allele-specific antibody; SLA, swine leukocyte antigen; PBMC, peripheral blood tion (8). We have now used this technique to study the basis of the mononuclear cells; Treg; regulatory T cell; VTL, vascularized thymic lobe; PCNA, prolifer- immunologic consequences of aging on the thymus. For this ating cell nuclear antigen; c/m, cortical/medullary. purpose, we transplanted vascularized thymic lobe (VTL) grafts *To whom correspondence should be addressed. E-mail: [email protected]. from aged miniature swine to young animals of the same swine This article contains supporting information online at www.pnas.org/cgi/content/full/ leukocyte antigen (SLA) inbred line (9). As we report here, these 0605159103/DC1. aged, involuted VTL grafts underwent rejuvenation after this © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0605159103 PNAS ͉ December 12, 2006 ͉ vol. 103 ͉ no. 50 ͉ 19081–19086 Downloaded by guest on September 26, 2021 Fig. 3. Representative histology of VTL grafts. H&E staining (ϫ40) of biopsy samples from an aged VTL graft (from a 20-month-old donor) in a juvenile Fig. 1. Morphometric analysis and histology of naive thymus at various 4-month-old recipient pig on day 0 (c/m ratio 0.79) (A), day 60 (c/m ratio 2.68) stages. (A) Morphometric analysis showing c/m areas of porcine thymus at (B), and day 100 (c/m ratio 3.62) (C). various times during the aging process. Histologic findings of porcine thymus at 4 months (H&E, ϫ100) (B) and 20 months (H&E, ϫ100) (C) of age. Cortical regions contain small, dense thymocytes showing strong hematophilic stain- PCNA on cytokeratin-positive cells in both the cortical and med- ing (c) compared with medullary regions (m). ullary regions increased to a maximum on day 100 (SI Fig. 6 D and F), indicating that active proliferation of thymic epithelial cells occurred. After day 100, the expression of PCNA decreased in a volute, with the c/m ratios on day 240 resembling those of recipient- pattern similar to the expression of PCNA in a naive, age-matched age-matched naive animals at these time points (Fig. 2). Fig. 3 shows thymus. the histology of biopsy specimens from one representative thymec- Cells dispersed from thymic biopsy tissues were also analyzed tomized juvenile animal (recipient 1) that received an aged thymic by flow cytometry by using allele-specific antibodies. Whereas all graft (c/m ratio of 0.79). By 60 days after transplant, the cortical of the thymocytes on day 0 were donor-type cells [negative for thymus had markedly expanded with larger lobular structures and pig allele-specific antigen (PAA)], most of the thymocytes in the well defined cortical and medullary regions (Fig. 3B). The animal day 60 VTL graft were recipient-type cells (PAA-positive) (SI maintained a thymic architecture that resembled that of a juvenile Fig. 7a). All thymocytes in the VTL graft were recipient type by animal until day 180 [Fig. 3C and supporting information (SI) Fig. day 100. The day 100 analysis revealed a phenotypic pattern 6A]. By day 240 (SI Fig. 6B), the cortical thymus of the grafts similar to that of a naive 4-month-old thymus (SI Fig. 7a). seemed to be thinner. This reinvolution was likely due to the Furthermore, the FACS profile of the thymocytes from aged recipient’s age, not to immunologic causes, because the thymi of thymic grafts on day 60 and thereafter revealed that a majority naive pigs also involute at this age (Fig.
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