Integrin Antagonists for Transplant Immunosuppression: Panacea or Peril?

Kitchens, William H.; Larsen, Christian; Ford, Mandy L.

doi:10.2217/imt.10.113

Cited by 13 publications

(13 citation statements)

References 20 publications

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“…Furthermore, the risk-benefit calculus of using efalizumab may be notably different in the setting of transplantation compared to psoriasis. If a combined regimen of belatacept and efalizumab could avert graft loss from CoB-resistant heterologous immune responses, it might justify a nominal absolute risk of PML (56). Future non-human primate trials with anti-LFA-1 and belatacept immunosuppression may better evaluate the clinical potential of this promising regimen of combined costimulatory and LFA-1 blockade, and to define its potential risks.…”

Section: Discussionmentioning

confidence: 99%

Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

Kitchens

Haridas²,

Wagener³

et al. 2012

Transplantation

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Background Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection cross-react with donor antigens. Due to their diminished requirements for costimulation during recall, these pathogen-elicited allo-crossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy. Methods We utilized an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor. Results We demonstrate that coupling the integrin antagonist anti-LFA-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP3+ Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone. Conclusions As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials.

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Section: Discussionmentioning

confidence: 99%

Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

Kitchens

Haridas²,

Wagener³

et al. 2012

Transplantation

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“…The control of memory alloreactive T cells, whether having arisen by heterologous immunity or other means, by blocking adhesion molecules has successfully been demonstrated in non-human primate transplantation models. Antibodies directed against lymphocyte function-associated antigen 1 (LFA1) (efalizumab), VLA4 (natalizumab) and the LFA3–immunoglobulin fusion protein (Alefacept) effectively prevented acute rejection of kidney or islet transplants in mice and non-human primates but also diminished protective memory to subsequent infections 95-98 , underscoring the potential limitation of this approach. Indeed, efalizumab and natalizumab have been associated with increased risk of progressive multifocal leukoencephalopathy (PML), and efalizumab has been withdrawn from the US market 98 .…”

Section: Implications For Therapymentioning

confidence: 99%

“…Antibodies directed against lymphocyte function-associated antigen 1 (LFA1) (efalizumab), VLA4 (natalizumab) and the LFA3–immunoglobulin fusion protein (Alefacept) effectively prevented acute rejection of kidney or islet transplants in mice and non-human primates but also diminished protective memory to subsequent infections 95-98 , underscoring the potential limitation of this approach. Indeed, efalizumab and natalizumab have been associated with increased risk of progressive multifocal leukoencephalopathy (PML), and efalizumab has been withdrawn from the US market 98 . These infectious concerns prompt the consideration of alternative approaches to minimize the impact of alloreactive memory T cells, such as through the selection of donor-recipient pairs with minimal pre-transplant memory donor-specific T cell reactivity 17 .…”

Section: Implications For Therapymentioning

confidence: 99%

The impact of infection and tissue damage in solid-organ transplantation

2012

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Preface Investigations over the past two decades are revealing the complexity in the regulation of the innate immune response, and how it, in turn, modulates adaptive immunity. Microbial exposure and tissue damage that accompany transplantation result in the release of both pathogen- and damage-associated molecular patterns, as well as the generation of cross-reactive alloreactive T cells. Here, we review these triggers of innate and adaptive immunity in the context of transplantation, and discuss the many ways infections and tissue damage might impact on alloreactivity and the outcome of transplanted allografts.

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“…However, anti-TCR mAbs have been largely neglected in clinical use, and anti-LFA1 mAb was recently removed from the market in 2009 for its risk of reactivation of latent JC virus infection [45], [46]. Recently, there has been renewed interest in the use of anti-LFA1 mAb in short-term settings or in combinations that can reduce its dosing regimen [47]. Our results indicate that the combination of these two agents provides a significant benefit for prolonging skin allograft survival in mice.…”

Section: Discussionmentioning

confidence: 99%

Transient Combination Therapy Targeting the Immune Synapse Abrogates T Cell Responses and Prolongs Allograft Survival in Mice

et al. 2013

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T cells play a major role in allograft rejection, which occurs after T cell activation by the engagement of several functional molecules to form an immune synapse with alloantigen presenting cells. In this study, the immune synapse was targeted using mAbs directed to the TCR beta-chain (TCRβ) and lymphocyte function-associated antigen−1 (LFA1) to induce long-term allograft survival. Evaluation of antigen-specific T cell responses was performed by adoptively transferring CFSE labeled transgenic OT-II cells into wild-type mice and providing OVA peptide by intravenous injection. Graft survival studies were performed in mice by transplanting BALB/c ear skins onto the flanks of C57BL/6 recipients. The anti-TCRβ plus anti-LFA1 mAb combination (but not either mAb alone) abrogated antigen-specific T cell responses invitro and invivo. Transient combination therapy with these agents resulted in significantly prolonged skin allograft survival in mice (51±10 days; p<0.01) when compared to treatment with either anti-TCRβ mAb (24±5 days) or anti-LFA1 mAb (19±3 days) alone or no treatment (10±1 days). When lymphoid tissues from these mice were analyzed at different times post-transplant, only those receiving the combination of anti-TCRβ and anti-LFA1 mAbs demonstrated long-lasting reductions in total T cell numbers, cellular and humoral anti-donor responses, and expression of CD3 on the surface of T cells. These results demonstrate that transient anti-TCRβ and anti-LFA1 mAb combination therapy abrogates antigen-reactive T cell responses with long-lasting effects that significantly prolong allograft survival.

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Integrin Antagonists for Transplant Immunosuppression: Panacea or Peril?

Cited by 13 publications

References 20 publications

Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

Combined Costimulatory and Leukocyte Functional Antigen-1 Blockade Prevents Transplant Rejection Mediated by Heterologous Immune Memory Alloresponses

The impact of infection and tissue damage in solid-organ transplantation

Transient Combination Therapy Targeting the Immune Synapse Abrogates T Cell Responses and Prolongs Allograft Survival in Mice

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