Combined effects of calcineurin inhibitors or sirolimus with anti-CD40L mAb on alloengraftment under nonmyeloablative conditions

Taylor, Patricia A.; Lees, Christopher J.; Wilson, Jessica; Ehrhardt, Michael; Campbell, Matthew T.; Noelle, Randolph J.; Blazar, Bruce R.

doi:10.1182/blood-2002-03-0872

Cited by 90 publications

(41 citation statements)

References 34 publications

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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].…”

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confidence: 99%

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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: Discussionmentioning

confidence: 99%

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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“…These data are similar to the observations made by Taylor et al in normal mice, where host signaling via a CD152-dependent pathway to generate regulatory T cells was required for the engraftment-promoting effect of anti-CD154 mAb for bone marrow. 12 Clearly, an understanding of the mechanism by which antigen-specific approaches promote HSC engraftment is critical to the potential clinical application of this approach, especially in autoimmune recipients.…”

Section: Discussionmentioning

confidence: 99%

“…7 Blocking CD40-CD40L costimulation through anti-CD154 mAb decreases TBI dose to 400 cGy, 11 and the addition of cyclosporine A further decreases the TBI dose to 200 cGy. 12 Nonobese diabetic (NOD) mice share with humans with type 1 diabetes at least 20 genetic loci associated with diabetes. 13,14 The underlying autoimmunity is associated with a number of features that differ from normal mice.…”

Section: Introductionmentioning

confidence: 99%

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Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

Ildstad

Chilton

et al. 2005

Blood

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Bone marrow transplantation blocks diabetes pathogenesis and reverses autoimmunity in nonobese diabetic (NOD) mice. However, there is a greater barrier to engraftment in the context of autoimmunity. In the present study, we characterized which recipient cells influence engraftment in prediabetic NOD mice, with the goal to replace myelotoxic conditioning with antigen-specific deletion of reactive host cells. Preconditioning of NOD mice with anti-CD8 and anti-CD154 monoclonal antibodies (mAbs) synergistically enhanced engraftment and significantly reduced the minimum total body irradiation (TBI) dose for engraftment. Strikingly, preconditioning with anti-CD4 mAb significantly impaired engraftment, negating the beneficial effect of anti-CD8, and resulted in a requirement for more TBIbased conditioning compared with controls conditioned with TBI alone. Similarly, more TBI was required when anti-Tcell receptor ␤ (TCR␤) mAb was administered as preconditioning. The addition of anti-CD152 to CD154 preconditioning abrogated the engraftmentenhancing effect of anti-CD154. Taken together, these data indicate a role for CD4 ؉ regulatory T cells in vivo which require signaling via CD152 in the induction of chimerism and tolerance in NOD recipients. Notably, disease prevention and reversal of autoimmunity was absolutely correlated with the establishment of chimerism. These studies have important implications for the design of novel clinical approaches to treat type 1 diabetes. IntroductionType 1 diabetes is an immune-mediated disorder associated with defects in the hematopoietic stem cell (HSC) and/or its progeny. A number of autoimmune diseases have been successfully treated via bone marrow transplantation (BMT) in rodents and humans. [1][2][3] Both full 2,4 and mixed 5 allogeneic chimerism interrupts disease progression and reverses the autoimmune pathogenesis. 2,4 Theoretically, BMT can be applied to treat type 1 diabetes via 2 mechanisms: (1) through reversal of the autoimmune processes that lead to islet cell destruction; and (2) through the induction of donorspecific tolerance to islet cell transplants. The morbidity and mortality associated with current conditioning methods has precluded the widespread use of BMT clinically. 6 Conditioning for BMT has historically been believed to require cytoreduction to prepare vacant niches and immunosuppression to suppress host-versus-graft alloreactivity. Current cytoreductive approaches use agents with broad and nonspecific myelotoxicity. The relative contribution of myelotoxic agents to preparing vacant niches versus controlling the host-versus-graft response is currently controversial. Recent data from nonmyeloablative conditioning models in nonautoimmune recipients suggest that the main role of myelotoxic agents is to control host-versus-graft alloreactivity rather than prepare vacant niches, 7,8 leading to the possibility of developing more benign antigen-driven conditioning strategies. For example, when total body irradiation (TBI) is used as the sole conditioning agent for ...

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Overview of Hematopoietic Cell Transplantation Immunology

Martin¹

2003

Thomas' Hematopoietic Cell Transplantation

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Combined effects of calcineurin inhibitors or sirolimus with anti-CD40L mAb on alloengraftment under nonmyeloablative conditions

Cited by 90 publications

References 34 publications

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

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

Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

Overview of Hematopoietic Cell Transplantation Immunology

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