Induction of Donor-Specific Unresponsiveness by Intrathymic Islet Transplantation

Posselt, Andrew M.; Barker, Clyde F.; Tomaszewski, John E.; Markmann, James F.; Choti, Michael A.; Naji, Ali

doi:10.1126/science.2119056

Cited by 355 publications

(127 citation statements)

References 19 publications

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“…Specific deficiency in thymic NKT cells is relevant to the immunopathology seen in this mouse [6,7]; NOD thymocytes produce low amounts of IL-4 [8], respond poorly to cytokines [9] and are relatively insensitive to apoptotic signals [10,11]. Experiments with F1 chimeras showed that the hemopoietic-derived thymic microenvironment is essential for development of diabetes [12,13] and intrathymic injection of Langerhans' islets abrogates autoimmunity [14]. Furthermore, although neonatal thymectomy prevents the appearance of diabetes, thymus ablation at weaning accelerates the disease [15], suggesting the existence of intrathymic regulatory cells.…”

Section: Introductionmentioning

confidence: 99%

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

et al. 2004

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We previously showed intrathymic alterations in non-obese diabetic (NOD) mice, including the appearance of giant perivascular spaces, filled with mature thymocytes, intermingled with an extracellular matrix network. This raised the hypothesis of a defect in thymocyte migration with partial arrest of exiting thymocytes in the perivascular spaces. Herein, we investigated the expression of receptors for fibronectin [very late antigen (VLA)-4 and VLA-5] and laminin (VLA-6), known to play a role in thymocyte migration. When compared with two normal and one other autoimmune mouse strains, a decrease of VLA-5 expression in NOD thymocytes was noticed, being firstly observed in late CD4/CD8 double-negative cells, and more pronounced in mature CD4 + and CD8 + thymocytes. Functionally, thymocyte exit from the lymphoepithelial complexes, the thymic nurse cells, was reduced. Moreover, NOD thymocyte adhesion to thymic epithelial cells as well as to fibronectin was diminished, and so was the migration of NOD thymocytes through fibronectin-containing transwell chambers. In situ, intra-perivascular space thymocytes were VLA-5-negative, suggesting a correlation between the thymocyte arrest within these structures and loss of VLA-5 expression. Overall, our data reveal impairment in NOD thymocyte migration, and correspond to the first demonstration of a functional fibronectin receptor defect in the immune system.

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Section: Introductionmentioning

confidence: 99%

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

et al. 2004

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“…Our laboratory has previously reported that inoculation of donor Ags into the recipient thymus can promote donor-specific tolerance (2)(3)(4)(5). Although the mechanism underlying this finding remains unknown, several hypotheses have been put forward to explain the phenomenon.…”

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confidence: 99%

CD25+ Immunoregulatory CD4 T Cells Mediate Acquired Central Transplantation Tolerance

Trani

Moore

Jarrett

et al. 2003

The Journal of Immunology

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Transplantation tolerance is induced reliably in experimental animals following intrathymic inoculation with the relevant donor strain Ags; however, the immunological mechanisms responsible for the induction and maintenance of the tolerant state remain unknown. We investigated these mechanisms using TCR transgenic mice (TS1) that carry T cells specific for an immunodominant, MHC class II-restricted peptide (S1) of the influenza PR8 hemagglutinin (HA) molecule. We demonstrated that TS1 mice reject skin grafts that have transgene-encoded HA molecules (HA104) as their sole antigenic disparity and that intrathymic but not i.v. inoculation of TS1 mice with S1 peptide induces tolerance to HA-expressing skin grafts. Intrathymic peptide inoculation was associated with a dose-dependent reduction in T cells bearing high levels of TCR specific for HA. However, this reduction was both incomplete and transient, with a full recovery of S1-specific thymocytes by 4 wk. Peptide inoculation into the thymus also resulted in the generation of immunoregulatory T cells (CD4+CD25+) that migrated to the peripheral lymphoid organs. Adoptive transfer experiments using FACS sorted CD4+CD25− and CD4+CD25+ T cells from tolerant mice revealed that the former but not the latter maintain the capacity to induce rejection of HA bearing skin allografts in syngeneic hosts. Our results suggest that both clonal frequency reduction in the thymus and immunoregulatory T cells exported from the thymus are critical to transplantation tolerance induced by intrathymic Ag inoculation.

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“…Following the report of intrathymic injection (IT) of pancreas islets [19], which induced generalized unresponsiveness as well as normalization of high blood-glucose levels in diabetic rats, the thymus has often been taken as an effective site for inoculating allogeneic cells in order to try to induce unresponsiveness. Many groups have recently demonstrated that tolerance to rat cardiac allografts by the IT of donor splenocytes [12,161 or bone marrow cells (BMCs) [14] can be induced.…”

Section: Introductionmentioning

confidence: 99%

Suppressed alloreactivity and mixed chimerism in rats with accepted cardiac allografts by intrathymic injection of donor bone marrow cells

Matsuura¹,

Imanishi²,

Hara³

et al. 1997

Transplant International

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Intrathymic injection of donor bone marrow cells (ITBMCs) at the time of transplantation and treatment with antilymphocyte serum (ALS) permitted the indefinite survival of Brown Norway (BN, RT1") rat heart grafts in 6 out of 8 Lewis (LEW, RT1') rat recipients. LEW recipients with long-surviving BN heart grafts (LSGs) also accepted additional BN heart grafts without further immunosuppression, though they rejected Piebald Virol Glaxo (PVG, RT1') rat heart grafts in the usual fashion. In the in vitro study, the proliferative response of the lymphocytes from LEW recipients with LSGs remained suppressed when they were stimulated by BN spleen cells, but not when stimulated by PVG cells. Bone marrow cells (BMCs) from LEW rats with LSGs showed strong, nonspecific, suppressive effects on the proliferative response in the mixed lymphocyte culture reaction, suggesting that one of the possible explanations for tolerance might be the involvement of a suppressor mechanism.

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Induction of Donor-Specific Unresponsiveness by Intrathymic Islet Transplantation

Cited by 355 publications

References 19 publications

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

Impaired migration of NOD mouse thymocytes: a fibronectin receptor‐related defect

CD25+ Immunoregulatory CD4 T Cells Mediate Acquired Central Transplantation Tolerance

Suppressed alloreactivity and mixed chimerism in rats with accepted cardiac allografts by intrathymic injection of donor bone marrow cells

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