Occasional reactions to papers and ideas worth thinking about out loud, cross-posted from LinkedIn.
PD-1 CAR T cells for MS — and a comparison to our skin data
A masterful and technically unbelievably impressive study from Ido Amit's lab identifies a rare population of chronically activated PD-1+ Tfh-like CD4 T cells in the cerebrospinal fluid of people with multiple sclerosis, then engineers PD-1-directed CAR T cells that suppress disease in a mouse model. We see a strikingly similar PD-1+ Tfh-like population in our own skin autoinflammation data — but without the corresponding B-cell expansion or IL-10 program described here, which raises the question of what tissue-specific conditions permit that difference.
What NIH funding history says about where biomedical innovation starts
Prompted by an op-ed arguing that private investment could replace the NIH as an engine of biomedical innovation, I traced the funding history behind checkpoint inhibitors, now central to cancer immunotherapy. More than a decade of NIH-funded basic research on T-cell activation and tolerance, led early on by NIAID rather than NCI, preceded any company deciding to develop a CTLA-4 or PD-1 antibody. Industry was indispensable in turning the discoveries into medicines, but the opportunity it pursued had already been sustained for years by public funding.
Could autoimmune disease develop like cancer, through stepwise somatic evolution?
A paper by Nicola et al. led me to Christopher Goodnow's 2007 proposal that autoimmune disease might develop the way cancer does: through the stepwise accumulation of events that let self-reactive clones escape immune checkpoints, rather than a single environmental trigger acting on genetic risk. Using highly accurate whole-exome sequencing, the authors found hundreds of independent B-cell clones with recurrent loss-of-function mutations in TNFRSF14 and CD274 in autoimmune thyroid disease, even in Hashimoto's, usually considered T-cell-mediated. It points toward a more testable framework: asking which inflammatory events act on which somatic alterations to push a clone into disease.
Commentary
Notes on papers and ideas
Occasional reactions to papers and ideas worth thinking about out loud, cross-posted from LinkedIn.
PD-1 CAR T cells for MS — and a comparison to our skin data
A masterful and technically unbelievably impressive study from Ido Amit's lab identifies a rare population of chronically activated PD-1+ Tfh-like CD4 T cells in the cerebrospinal fluid of people with multiple sclerosis, then engineers PD-1-directed CAR T cells that suppress disease in a mouse model. We see a strikingly similar PD-1+ Tfh-like population in our own skin autoinflammation data — but without the corresponding B-cell expansion or IL-10 program described here, which raises the question of what tissue-specific conditions permit that difference.
What NIH funding history says about where biomedical innovation starts
Prompted by an op-ed arguing that private investment could replace the NIH as an engine of biomedical innovation, I traced the funding history behind checkpoint inhibitors, now central to cancer immunotherapy. More than a decade of NIH-funded basic research on T-cell activation and tolerance, led early on by NIAID rather than NCI, preceded any company deciding to develop a CTLA-4 or PD-1 antibody. Industry was indispensable in turning the discoveries into medicines, but the opportunity it pursued had already been sustained for years by public funding.
Could autoimmune disease develop like cancer, through stepwise somatic evolution?
A paper by Nicola et al. led me to Christopher Goodnow's 2007 proposal that autoimmune disease might develop the way cancer does: through the stepwise accumulation of events that let self-reactive clones escape immune checkpoints, rather than a single environmental trigger acting on genetic risk. Using highly accurate whole-exome sequencing, the authors found hundreds of independent B-cell clones with recurrent loss-of-function mutations in TNFRSF14 and CD274 in autoimmune thyroid disease, even in Hashimoto's, usually considered T-cell-mediated. It points toward a more testable framework: asking which inflammatory events act on which somatic alterations to push a clone into disease.