Insulin-dependent diabetes may occur in patients with cancers who are treated with checkpoint inhibitors (CPIs). We reviewed cases occurring over a 6-year period at two academic institutions and identified 27 patients in whom this developed, or an incidence of 0.9%. The patients had a variety of solid-organ cancers, but all had received either anti-PD-1 or anti-PD-L1 antibodies. Diabetes presented with ketoacidosis in 59%, and 42% had evidence of pancreatitis in the peridiagnosis period. Forty percent had at least one positive autoantibody and 21% had two or more. There was a predominance of HLA-DR4, which was present in 76% of patients. Other immune adverse events were seen in 70%, and endocrine adverse events in 44%. We conclude that autoimmune, insulin-dependent diabetes occurs in close to 1% of patients treated with anti-PD-1 or -PD-L1 CPIs. This syndrome has similarities and differences compared with classic type 1 diabetes. The dominance of HLA-DR4 suggests an opportunity to identify those at highest risk of these complications and to discover insights into the mechanisms of this adverse event.
Background
Cardiac allograft vasculopathy (CAV) is the major cause of late allograft loss following heart transplantation. CAV lesions contain alloreactive T cells that secrete IFN-γ, a vasculopathic cytokine, and occur more frequently in patients with donor specific antibody (DSA). Pathologic interactions between these immune effectors, representing cellular and humoral immunity, respectively, remain largely unexplored.
Methods and Results
We used human panel reactive antibody (PRA) to form membrane attack complexes (MAC) on allogeneic endothelial cells in vitro and in vivo. Rather than inducing cytolysis, MAC upregulated inflammatory genes, enhancing the capacity of EC to recruit and activate allogeneic IFN-γ-producing CD4+ T cells in a manner dependent upon activation of non-canonical NF-κB signaling. Non-canonical NF-κB signaling was detected in situ within EC both in renal biopsies from transplant patients with chronic antibody-mediated rejection and in PRA-treated human coronary artery xenografts in immunodeficient mice. Upon re-transplantation into immunodeficient hosts engrafted with human T cells, PRA-treated grafts recruited more IFN-γ-producing T cells and enhanced CAV lesion formation.
Conclusions
Alloantibody and complement deposition on graft EC activate non-canonical NF-κB signaling, initiating a pro-inflammatory gene program that enhances alloreactive T cell activation and development of CAV. Non-canonical NF-κB signaling in EC, observed in human allograft specimens and implicated in lesion pathogenesis, may represent a target for new pharmacotherapies to halt the progression of CAV.
The characteristics of tetrahydrobiopterin (H4biopterin) binding to pteridine-free recombinant macrophage inducible nitric oxide synthase expressed in Escherichia coli were investigated with a special focus given to effects caused by 2,4-diamino-5,6,7, 8-tetrahydro-6-(l-erythro-1,2-dihydroxypropyl)pteridine (4-amino-H4biopterin), a novel pterin-based inhibitor of nitric oxide synthase. The 4-amino compound completely inhibited enzyme stimulation by 10 microM H4biopterin with a half-maximally active concentration of 7.2 +/- 0.39 microM, whereas H2biopterin and sepiapterin were much less potent. Binding studies using [3H]H4biopterin at 4 degrees C revealed biphasic association of the radioligand according to two first-order reactions with apparent rate constants of 2.2 and 0.05 min-1, each accounting for approximately 50% of total binding. Dissociation of [3H]H4biopterin occurred with rate constants of 0.005 and 0.0028 min-1 in the absence and presence of l-arginine, respectively. Specific binding of 10 nM [3H]H4biopterin was antagonized by unlabeled H4biopterin and its 4-amino analog with half-maximal effects at 84 +/- 6 and 34 +/- 3.2 nM, respectively. Binding of H4biopterin and 4-amino-H4biopterin was accompanied by a partial low spin to high spin conversion of the heme that was completed by l-arginine. Similarly, the active cofactor and the inhibitory 4-amino derivative both induced significant formation of stable protein dimers that survived during SDS electrophoresis, suggesting that the allosteric effects caused by H4biopterin do not explain sufficiently the essential role of the pteridine cofactor in NO biosynthesis.
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