Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Laughlin, Elsa M.; Burke, George W.; Pugliese, Alberto; Falk, Ben; Nepom, Gerald T.

doi:10.1016/j.clim.2008.03.459

Cited by 72 publications

(60 citation statements)

References 21 publications

(23 reference statements)

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“…Persistence of autoantibodies did not confer increased risk. While previous studies have noted associations of autoantibodies with graft failure 25, 29, our study is the first to link autoantibodies specifically to biopsy‐confirmed T1D recurrence, and in our own ongoing studies these are being linked to autoimmune T cell responses (Table S1A) 11, 42.…”

Section: Discussionmentioning

confidence: 61%

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Vendrame

Hopfner

Diamantopoulos

et al. 2016

American Journal of Transplantation

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Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas–kidney allografts for T1D recurrence and its risk factors. With long‐term follow‐up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D‐associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor–recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D‐predisposing HLA‐DR3/DR4 genotype in the recipient and donor–recipient sharing of HLA‐DR alleles, especially HLA‐DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.

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Section: Discussionmentioning

confidence: 61%

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Vendrame

Hopfner

Diamantopoulos

et al. 2016

American Journal of Transplantation

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“…The recognition of the role of islet autoreactive CD4+ T cells [22,23] and CD8+ T cells [27,30] on beta-cell destruction, as well as all the targets of humoral activity [28] , may lead to other treatment opportunities. Novel therapies, namely targeting proinsulin-reactive CD8+ T cells, were recently pro-posed as a potential therapeutic approach [31] .…”

Section: Resultsmentioning

confidence: 99%

“…The Miami group has tried to treat autoimmune relapse in pancreas transplants with anti-lymphocyte (anti-B and/or anti-T cell) therapies [21][22][23] . After a transient response in a few cases, autoimmune activity has recurred within a short period of time.…”

Section: Immunosuppression and Autoimmunitymentioning

confidence: 99%

Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation

Martins¹

2014

WJT

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Autoimmune type 1 diabetes recurrence in pancreas grafts was first described 30 years ago, but it is not yet completely understood. In fact, the number of transplants affected and possibly lost due to this disease may be falsely low. There may be insufficient awareness to this entity by clinicians, leading to underdiagnosis. Some authors estimate that half of the immunological losses in pancreas transplantation are due to autoimmunity. Pancreas biopsy is the gold standard for the definitive diagnosis. However, as an invasive procedure, it is not the ideal approach to screen the disease. Pancreatic autoantibodies which may be detected early before graft dysfunction, when searched for, are probably the best initial tool to establish the diagnosis. The purpose of this review is to revisit the autoimmune aspects of type 1 diabetes and to analyse data about the identified autoantibodies, as serological markers of the disease. Therapeutic strategies used to control the disease, though with unsatisfactory results, are also addressed. In addition, the author's own experience with the prospective monitoring of pancreatic autoantibodies after transplantation and its correlation with graft outcome will be discussed.

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“…This phenomenon of selective destruction of beta cells was also observed in recipients of cadaveric pancreatic grafts [36] and in recipients of islet allografts [37] without evidence of alloimmune rejection [34][35][36]. Further studies strongly suggested that recurrence of T1D autoimmunity was due to autoreactive, antigenspecific memory CD8 + and CD4 + T cells after islet and pancreas transplantation [37][38][39][40]. In a multicenter, randomized, double-blind, placebo-controlled clinical trial of recent onset T1D patients, treatment with alefacept, preserved their C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at one year, even after one year of termination of therapy.…”

Section: Successesmentioning

confidence: 76%

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

Zaidi¹,

Meng²

2016

Immunother Open Acc

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Current anti-retroviral treatment (ART) for HIV is effective in maintaining HIV at undetectable levels. However, cessation of ART results in immediate and brisk rebound of viremia to high levels. This rebound is driven by an HIV reservoir mainly enriched in memory CD4 + T cells. In order to provide any form of functional HIV Cure, elimination of this viral reservoir has become the focus of current HIV cure strategies. Alefacept was initially developed for the treatment of chronic plaque psoriasis. Alefacept is a chimeric fusion protein consisting of the CD2-binding portion of human leukocyte function antigen-3 (LFA3) linked to the Fc region of human IgG1 (LFA3-Fc). Alefacept was designed to inhibit memory T cell activation that contributes to the chronic autoimmune disease psoriasis by blocking the CD2 coreceptor. However, it was found to deplete memory T cells that express high levels of CD2 via NK cellmediated antibody dependent cell cytotoxicity (ADCC) in vivo. Phase II and phase III clinical trials of alefacept with psoriasis patients demonstrated promising results and an excellent safety profile. Subsequently, alefacept has been successfully repurposed for other memory T cell-mediated autoimmune diseases including skin diseases other than psoriasis, organ transplantation and type I diabetes (T1D). Herein, we review our specific strategy to repurpose the FDA approved biologic alefacept to decrease and hopefully someday eliminate the HIV reservoir, for which CD2 hi memory CD4 + T cells are a significant contributor.

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Recurrence of autoreactive antigen-specific CD4+ T cells in autoimmune diabetes after pancreas transplantation

Cited by 72 publications

References 21 publications

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

Autoimmune diabetes recurrence should be routinely monitored after pancreas transplantation

Can We Repurpose FDA-Approved Alefacept to Diminish the HIV Reservoir?

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