Host Genetics May Affect aGVHD Risk
Rashidi A, Shanley R, Yohe SL, et al. Recipient Single Nucleotide Polymorphisms in Paneth Cell Antimicrobial Peptide Genes and Acute Graft-Versus-Host Disease. British Journal of Haematology. 2018; 182 (6): 887 (doi: 10.1111/bjh.15492).
New research suggests host genetics may influence acute graft-versus-host disease (aGVHD) risk by modulating Paneth cell function. Knowing that the risk of acute graft-versus-host disease (aGVHD) is influenced by gut dysbiosis and that immune regulation is contributed to by Paneth cell and microbiota interactions, investigators evaluated single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) with regard to predicting aGVHD risk. They analyzed pre-transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced-intensity conditioning; all using peripheral blood grafts). Multivariable analysis showed DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II–IV in CTN-0201 (SNP x graft source interaction), but not CTN-0901 (SNP x conditioning intensity), indicating a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD.
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Myeloma Relapse Mechanism Proposed
Minnie SA, Kuns RD, Gartlan KH, et al. Myeloma-Escape After Stem Cell Transplantation Is a Consequence of T Cell Exhaustion and Is Prevented by TIGIT Blockade. Blood. 2018; (doi: 10.1182/blood-2018-01-825240).
New research suggests that programmed death 1 (PD-1) or T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) blockade in conjunction with autologous stem cell transplantation (auto-SCT) may be a potent combination treatment approach for myeloma. Researchers used a preclinical mouse model of auto-SCT for myeloma where the disease either progressed (MM-relapsed) or was controlled to gain some understanding of the mechanism disease progression after auto-SCT. It was found that inhibitory receptor expression on bone marrow CD8+ T-cells correlated with myeloma progression after transplant and that co-stimulatory/adhesion receptor CD226 (DNAM-1) was markedly downregulated. Mice who relapsed were found to have an exhausted phenotype with upregulated TIGIT and PD-1. The use of immune checkpoint blockade monoclonal antibodies against PD-1 or TIGIT significantly prolonged myeloma control after SCT. It was also observed that CD8+ T-cells from MM-relapsed mice had high interleukin-10 (IL-10) secretion that was linked to greater TIGIT and PD-1 expression and, thus, promoted myeloma progression. These findings suggest the importance of PD-1 or TIGIT blockade along with auto-SCT in treatment of multiple myeloma.
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Notch Signaling Drives the Pathogenesis of cGVHD in Mice
Radojcic V, Paz K, Chung J, et al. Notch Signaling Mediated by Delta-like1/4 Ligands Controls the Pathogenesis of Chronic Graft-Versus-Host Disease in Mice. Blood. 2018; (doi: 10.1182/blood-2018-03-841155).
New evidence supports targeting individual Notch ligands and receptors for therapeutic intervention in the treatment or prevention of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplant (HCT). Researchers studied the role of Notch signaling in two mouse models that mimic several aspects of human cGVHD. In the model mimicking sclerodermatous cGVHD, Delta-like4 (Dll4)-driven Notch signaling was important for development of scleroderma, but if Dll4 was inhibited the disease development could be prevented. The second mouse model manifested multi-organ system cGVHD with bronchiolitis obliterans and not skin disease. Here durable protection from cGVHD was seen with the absence of Notch signaling in T cells. During established cGVHD, this protective effect was observed with targeting of Dll1, Dll4, or both Notch ligands. The results demonstrate that Notch inhibition plays a key role in preventing or treating various forms of cGVHD.
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