The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade

Blaha, Peter; Bigenzahn, Sinda; Koporc, Zvonimir; Schmid, Maximilian; Langer, Felix B.; Selzer, Edgar; Bergmeister, Helga; Wrba, Friedrich; Kurtz, Josef; Kiss, Christopher; Roth, Erich; Muehlbacher, Ferdinand; Sykes, Megan; Wekerle, Thomas

doi:10.1182/blood-2002-10-3014

Cited by 166 publications

(186 citation statements)

References 53 publications

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“…33,34 Rapamycin was supposed to contribute to tolerance induction by allowing activation induced cell death of effector cells. [35][36][37] We think that the contrasting effects of CsA and rapamycin on the generation and homeostasis of CD4 þ FoxP3 þ T REG that we describe here may offer additional explanations for the dissimilar influence of these drugs on tolerance induction in various models. In agreement with our findings, CsA treatment of newborn mice was found to cause autoimmune diseases similar to those observed following neonatal thymectomy, which also has a detrimental effect on T REG homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Coenen

Koenen

Rijssen

et al. 2007

Bone Marrow Transplant

146

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Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3 þ regulatory T-cell (T REG ) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T REG homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T REG homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4 þ CD25 þ FoxP3 þ T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25 þ FoxP3 þ T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4 þ FoxP3 þ T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4 þ FoxP3 þ T REG in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.

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Section: Discussionmentioning

confidence: 99%

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Coenen

Koenen

Rijssen

et al. 2007

Bone Marrow Transplant

146

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“…However, since there are also many studies using fully mismatched combinations that did not find split tolerance even with skin grafts given late after BMT [20,21,[46][47][48][49], other factors must also be involved. Rejection of skin grafts in chimeras can be quite a protracted process, and in many studies skin grafts are not followed sufficiently long [50].…”

Section: Discussionmentioning

confidence: 99%

“…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.However, since there are also many studies using fully mismatched combinations that did not find split tolerance even with skin grafts given late after BMT [20,21,[46][47][48][49], other factors must also be involved. Rejection of skin grafts in chimeras can be quite a protracted process, and in many studies skin grafts are not followed sufficiently long [50].…”

mentioning

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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“…In human settings, immunosuppressive treatments are mandatory, at least during the early phase of AHCT, until tolerance is fully established. Since immunosuppressive drugs are capable of interfering with long-term tolerance induction, 6 we investigated whether the widely used immunosuppressive drugs (cyclosporin A, CsA; mycophenolate mofetil, MMF or sirolimus, SRL) can modulate the effect of apoptotic cells coadministered with a hematopoietic graft in a murine BMT model.…”

mentioning

confidence: 99%

Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic engraftment and tolerance induction

et al. 2007

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The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade

Cited by 166 publications

References 53 publications

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

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

Sirolimus enhances the effect of apoptotic cell infusion on hematopoietic engraftment and tolerance induction

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