Innate Immune Activation by Tissue Injury and Cell Death in the Setting of Hematopoietic Stem Cell Transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with donor lymphocyte infusion is the mainstay of treatment for many types of hematological malignancies, but the therapeutic effect and prevention of relapse is complicated by donor T-cell recognition and attack of host tissue in a process known as graft-versus-host disease (GvHD). Cytotoxic myeloablative conditioning regimens used prior to Allo-HSCT result in the release of endogenous innate immune activators that are increasingly recognized for their role in creating a pro-inflammatory milieu. This increased inflammatory state promotes allogeneic T-cell activation and the induction and perpetuation of GvHD. Here, we review the processes of cellular response to injury and cell death that are relevant following Allo-HSCT and present the current evidence for a causative role of a variety of endogenous innate immune activators in the mediation of sterile inflammation following Allo-HSCT. Finally, we discuss the potential therapeutic strategies that target the endogenous pathways of innate immune activation to decrease the incidence and severity of GvHD following Allo-HSCT.

Infection with a respiratory virus before hematopoietic cell transplantation is associated with alloimmune-mediated lung syndromes

“…This concept fits the current understanding of alloimmunity after HCT, where host antigen-presenting cells are activated by danger signals expressed on damaged tissues, pathogens, or both, leading to alloactivation and cytokine release and inducing a cycle of inflammation and tissue damage. [24][25][26] Therefore further studies on the influence of the microbiome/viriome on the development of alloreactive immune phenomena after HCT are of great interest. In line with this, in patients with an inborn error of metabolism, which was found to be a borderline predictor for IPS, storage of glycosaminoglycans in the lungs can lead to low-grade inflammation and activation of antigen-presenting cells as well.…”

Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses

“…Likewise, SOTx and allogeneic hematopoietic cell transplantation (AlloHCT) may utilize induction protocols containing irradiation or therapeutic agents that cause dramatic cell death in recipient tissues, particularly the epithelium (10). Immunosuppressants, as well as leukocyte targeting antibodies, mediate the destruction of recipient leukocytes, as well as other recipient cells.…”

“…Multiple processes involved in SOT, such as surgical procedures and associated ischemia-reperfusion injury (IRI) as well as recipient alloimmune responses, initiate a sterile inflammatory process that would not be associated with release of PAMPs (9). Likewise, SOT and allogeneic hematopoietic cell transplantation (alloHCT) may use induction protocols containing irradiation or therapeutic agents that cause dramatic cell death in recipient tissues, particularly the epithelium (10). Immunosuppressants and leukocytetargeting antibodies mediate the destruction of recipient leukocytes and other recipient cells.…”

“…Multiple extracellular cellular matrix (ECM) fragments also have been suggested to act as alarmins, particularly heparan sulfate proteoglycan, fibronectin, fibrinogen, hyaluronate, biglycan, tenascin and hyaluronan. Details of many proposed alarmins (Table 1) have been provided in recent reviews, with several discussing the impact of alarmins on the alloimmune responses leading to graft-versus-host disease (GVHD) (10,14,15). Rather than focusing on the general characterization of individual alarmins, we instead have discussed how an evolving understanding of alarmin immunobiology is being revealed in recent rodent studies, primarily examining the impact of HMGB1 or IL-33 on alloHCT and SOT.…”

Conditioning with Fludarabine-Busulfan versus Busulfan-Cyclophosphamide Is Associated with Lower aGVHD and Higher Survival but More Extensive and Long Standing Bone Marrow Damage

“…Pretransplantation conditioning provides space in the hematopoietic compartment for donor stem cells, eradicates residual leukemia/lymphoma cells, and provides immunosuppression to prevent graft failure [7]. The conditioning intensity is closely related to posttransplantation relapse and the development of aGVHD.…”