Complex interactions of cellular players in chronic Graft-versus-Host Disease

Abstract

Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes.

The role and novel use of natural killer cells in graft-versus-leukemia reactions after allogeneic transplantation

“…This period of immunosuppression is characterized by a high risk of bacterial and viral infections, including reactivation of opportunistic viruses like cytomegalovirus (CMV) ( 44 ). NK cells have an established role in anti-viral immunity, as demonstrated by the overwhelming viral infections associated with disorders marked by a congenital absence of NK cells ( 45 ). NK cells, as part of the innate immune system, play an important role in CMV control ( 44 , 46 ).…”

“…NK cells may also play an important role in the suppression and prevention of GVHD through lysis of responsible alloreactive T cells ( 45 – 48 ). Low total numbers of NK cells have been linked to poor GVHD outcomes including worse OS ( 45 , 49 ).…”

“…NK cells may also play an important role in the suppression and prevention of GVHD through lysis of responsible alloreactive T cells ( 45 – 48 ). Low total numbers of NK cells have been linked to poor GVHD outcomes including worse OS ( 45 , 49 ). However, there is also data that NK cell-mediated production of cytokines may contribute to the inflammatory cascade responsible for GVHD ( 45 ).…”

“…Low total numbers of NK cells have been linked to poor GVHD outcomes including worse OS ( 45 , 49 ). However, there is also data that NK cell-mediated production of cytokines may contribute to the inflammatory cascade responsible for GVHD ( 45 ). Interestingly, subtypes of NK cells have been identified in murine intestines that may play a role in protection against bacterial infections associated with development of gastrointestinal GVHD, through both cytokine-induced defenses and regeneration of the gut epithelium ( 47 ).…”

Osteoclasts and Probiotics Mediate Significant Expansion, Functional Activation and Supercharging in NK, γδ T, and CD3+ T Cells: Use in Cancer Immunotherapy

“…To date, NK cell-based immunotherapies have gained significant attention because many techniques were demonstrated for in vitro NK cell proliferation, resulting in higher NK cell numbers for therapeutics as well as increased in vivo functional activity and proliferation of NK cells [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. In addition, NK cells lack graft versus host disease (GVHD), which allows the use of autologous as well allogeneic NK cells for adoptive cell therapies [40][41][42][43].…”