Elsevier

Blood Reviews

Volume 30, Issue 3, May 2016, Pages 179-188
Blood Reviews

REVIEW
A promising sword of tomorrow: Human γδ T cell strategies reconcile allo-HSCT complications

https://doi.org/10.1016/j.blre.2015.11.002Get rights and content

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially a curative therapeutic option for hematological malignancies. In clinical practice, transplantation associated complications greatly affected the final therapeutical outcomes. Currently, primary disease relapse, graft-versus-host disease (GVHD) and infections remain the three leading causes of a high morbidity and mortality in allo-HSCT patients. Various strategies have been investigated in the past several decades including human γδ T cell-based therapeutical regimens. In different microenvironments, human γδ T cells assume features reminiscent of classical Th1, Th2, Th17, NKT and regulatory T cells, showing diverse biological functions. The cytotoxic γδ T cells could be utilized to target relapsed malignancies, and recently regulatory γδ T cells are defined as a novel implement for GVHD management. In addition, human γδ Τ cells facilitate control of post-transplantation infections and participate in tissue regeneration and wound healing processes. These features potentiate γδ T cells a versatile therapeutical agent to target transplantation associated complications. This review focuses on insights of applicable potentials of human γδ T cells reconciling complications associated with allo-HSCT. We believe an improved understanding of pertinent γδ T cell functions would be further exploited in the design of innovative immunotherapeutic approaches in allo-HSCT, to reduce mortality and morbidity, as well as improve quality of life for patients after transplantation.

Introduction

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is potentially a curative therapeutic option for patients suffering from hematological malignancies. Majorly benefiting from the enormous advances in novel conditioning regimens derived through unprecedented developments of immunological theories and transplantation techniques in recent years, allo-HSCT has been widely applied in clinical practice and benefited thousands of patients with malignant hematological disorders [1], [2]. In addition to conventional therapies for treatment-naïve patients, cutting-the-edge improvements in induction chemotherapy also salvage a greater number of patients with otherwise refractory or relapsed hematological malignancies, endowing more patients with the precious opportunity of taking life-saving allo-HSCT [3], [4]. Moreover, increasing cases covered by reduced-intensity and non-myeloablative conditioning protocols promoted allo-HSCT a favorable option for senile patients who were not qualified for allo-HSCT decades ago. Additionally, it is well known that a limited donor matching rate greatly halted clinical application of HSCT. In recent several years, bona fide outcomes achieved with unrelated and haploidentical donors as well as with cord blood grafts have indicated a reliable solution for more patients whose donors were previously unavailable [5], [6], [7]. Up to date, clinical experts have proved de facto that appropriate allograft manipulation in vitro, such as T-cell depletion, could greatly improve transplantation outcomes in certain recipients [8]. These advantages collectively demonstrate that allo-HSCT would be a rational strategy equivalent for auto-HSCT for patients of hematological malignancies in the future.

The overall outcomes of patients after allo-HSCT are greatly affected by certain complications. Despite the emergence of novel preventative and therapeutical regimens as well as advances of diagnostic strategies in clinical practice, the primary disease relapse, graft-versus-host disease (GVHD) and infection continue to be the three leading causes of morbidity and mortality in allo-HSCT patients [9]. According to CIBMTR statistical analysis, the primary disease relapse, occurred in about 37% unrelated donor transplantations and 49% in HLA-identical sibling transplantations, was the leading cause of death following allo-HSCT. GVHD accounting for about 18% in unrelated donor transplantations and 16% in HLA-identical sibling transplantations was listed as the second cause of death; while infection taking up about 18% in unrelated donor transplantations and 13% in HLA-identical sibling transplantations as the third cause of death in those patients [10]. Notably, secondary cancers including donor-derived malignancies are among the most threatening long-term potential issues after allo-HSCT [11]. As a matter of course, these high-risk complications inevitably affected the quality of life for recipients and the final therapeutical outcomes after allo-HSCT. Targeting implications after allo-HSCT for a better post-transplantational overall survival, active investigations in this field are being prompted on developing novel strategies, aiming to reduce pertinent risks of complications.

In allo-HSCT recipients, the immune reconstitution is a critical issue linked to therapeutic efficacy, associated complications and prognosis. Nearly two decades ago, researchers found that adaptive immune reconstitution in allo-HSCT patients was often delayed because of damaged thymic generation and outputs during transplantation procedures, which partially resulted in a lower survival rate [12], [13]. Recent clinical observations and studies demonstrated that reconstitution of innate immunity following transplantation was characteristically more rapid than that of the adaptive immune system, attributed to a fact that early innate immune reconstitution played vital roles in immunologic defense and surveillance [14], [15], [24]. A rapid immune reconstitution improved clinical outcomes in allo-HSCT patients. More important, it provides with a hinge that allo-HSCT patients might benefit from strategies to enhance adaptive immune reconstitution by stirring host immune systems, and potentiates immune regulation a favorable direction for the control of allo-HSCT associated complications.

In human immune systems, γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to various types of immune response and immunopathological processes [16]. In various microenvironments, γδ T cells tend to assume biological features reminiscent of classical Th1, Th2, Th17, NKT and regulatory T cells, as well as professional antigen presenting cells (Fig. 1). The plasticity and heterogeneity of γδ T cells imply diverse biological functions. First, these cells exerted anti-tumor activities against various types of solid tumors and hematological malignancies via in vitro and in vivo mechanisms including but not limited to perforin-mediated cytotoxic effects, contact-dependent trogocytosis, antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) [17], [18], [19]. Secondary, as the most abundant of all epithelial-resident lymphocytes and the first line of defense against pathogens in the mucosa, a group of γδ T cells also plays an indispensable role in host defense against different pathogens including viruses, bacteria and parasite [20]. Third, functional diverse γδ T cell subtypes have been verified to be involved in transplant tolerance induction both in solid organ transplantation and in allo-HSCT [21], [22]. The last but not the least, γδ T cells assist wound healing by providing keratinocyte and fibroblast growth factors [23]. Moreover, as for human γδ T cells, therapeutical protocols adopted in clinical trials by interleukin-2 (IL-2) combined with phosphoantigen or antibodies against TCR γδ have shown selective activation and expansion effects on Vγ9Vδ2 T cell subpopulations [24]. A rapid reconstitution of γδ T cells post-transplantation implied their favorable regulation in prevention and control of those high-risk complications following allo-HSCT. Consequently, the diverse and comprehensive immunobiological features of γδ T cells potentiate such cell populations a powerful targeting therapeutic strategy against allo-HSCT associated complications. An improved understanding of pertinent cellular function has been recently exploited in the design of innovative γδ T cell-based immunotherapeutic approaches in allo-HSCT, tending to reduce mortality and morbidity as well as improve quality of life post-transplantation. In this review, we focus on applicable potentials of human γδ T cells reconciling complications associated with allo-HSCT.

Section snippets

γδ T cell reconstitution: innate immunity prior to adaptive immunity

The ultimate goal of stem cell transplantation is the establishment of a nascent donor-derived cellular and humoral immunity in recipients. During the last decade, the reconstitution processes and patterns of cellular immunity after allo-HSCT, including cytotoxic lymphocytes and NK cells in the innate immune system, and several T cell subpopulations in the adaptive immune systems have been clarified. These findings have revealed the nature of immune reconstitution after allo-HSCT, guided

Cytotoxic γδ T cells to target relapse: the power on GVL effects

Human γδ T cells have been demonstrated to exert tumoricidal effects against hematological malignancies in vitro and in vivo, via directly recognizing targeting molecules expressed on leukemia cells in an MHC-independent manner. Moreover, γδ T cells can migrate as infiltrating lymphocytes into solid tumor tissues [28] and can also recognize and eliminate cultured malignant cells (primary cells or cell lines) from myeloma, leukemia and non-Hodgkin lymphoma as shown in Fig. 3 [29], [30], [31].

Regulatory γδ T cells: a fresh implement for GVHD management

The phenomena of γδ Τ cells in regulation of GVHD have been extensively studied but still remain unclear. There is a growing body of data suggesting that non-MHC-restricted killer cells may be involved in the pathogenesis of GVHD. γδ Τ cells bear immunobiological plasticity in at least two major forms, the acquired plasticity and the innate plasticity, which bestow them with a unique ability to carry out a restricted set of functions with spatial and temporal features (Fig. 4).

Surprisingly,

γδ Τ cells facilitate control of post-transplantation infections

Infectious diseases are usually the major post-transplantational threat to immune-compromised recipients. A long-term routine administration of antibiotics to control infections always induces potential emergency of drug resistance. In clinical practice, the multi-drug resistance to infectious pathogens has led to a high morbidity and mortality [70]. As a part of human cellular immune system, γδ Τ cells have been reported to play distinct roles against human infectious diseases caused by

γδ Τ cells facilitate tissue regeneration

The implementation of conditioning regimen, pathogenesis of GVHD and existence of potential infections following allo-HSCT could result in destruction of mucosal and epithelial tissues, contributing to a significant high morbidity and mortality. Accordingly, a rapid tissue repair process would significantly reduce magnitudes of destructions caused by physical and chemical damages in these immune-compromised patients. γδ T cells are constitutive resident lymphocytes in mucosal and epithelial

Perspectives: on-going tasks

Although our knowledge of the role of γδ T cells in human immunology is still incomplete, there are sufficient experimental, pre-clinical and clinical observational data to roughly justify the design of clinical protocols that involve the manipulation of human γδ T cells for the purpose of preventing or treating complications associated allo-HSCT. Important issues that can potentially reveal further functional insights into their roles in clinical allo-HSCT remain to be addressed include the

Practice points

  • Primary disease relapse, graft-versus-host disease (GVHD) and infection remain the three leading causes of high morbidity and mortality in allo-HSCT patients.

  • γδ T cell subsets exert anti-tumor activities, play an indispensable role in host defense against different pathogens, induce transplant tolerance and assist wound healing by providing keratinocyte and fibroblast growth factors.

  • γδ T cells have potential roles in targeting transplantation associated complications.

Research agenda

  • Improved understanding of biological characteristics of γδ T cell subsets.

  • γδ T cell manipulation for transplantation associated complications.

Conflict of interest

The authors declare no conflicts of interest.

Acknowledgments

This work was jointly supported by grants from Zhejiang Provincial Natural Science Foundation of China (LY14H080002, Y2110183), the National Natural Science Foundation of China (81470341, 81500157), Zhejiang Medical Technology & Education (201476288), Jinhua Administration of Science &Technology(2014-3-006), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (CQ2014), the Scientific Research Fund for Young Scientists, Beijing Tiantan

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