PD-1 and CTLA-4 up regulation on donor T cells is insufficient to prevent GvHD in allo-HSCT recipients.

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients.

A child with refractory complex partial seizures, right temporal ganglioglioma, contralateral continuous electrical status epilepticus, and a secondary Landau-Kleffner autistic syndrome.

A 7-year-old, right-handed girl started to have seizures at age 1 year 4 months. She developed normally until age 4 when she had worsening of seizures with auditory verbal agnosia, complete aphasia, and a behavioral disorder fulfilling the diagnostic criteria of autism. Medical therapy failed. MRI revealed a right temporal tumor. Video/EEG monitoring at age 7 showed contralateral electrical status epilepticus in wakefulness and sleep and ipsilateral onset of seizures. Resection (ganglioglioma with excessive inflammation) resulted in seizure freedom and marked reduction of the autistic features. This case is unique for being, to our knowledge, (1) the first in which a lesion located in the right, rather than left, temporal lobe resulted in secondary falsely localizing left temporal lobe electrical status epilepticus with a clinical picture of Landau-Kleffner syndrome and autism, and (2) the fourth reported patient with lesional Landau-Kleffner syndrome to respond to resective surgery.