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Homing in on Acute Graft vs. Host Disease: Tissue-Specific T Regulatory and Th17 Cells

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The Chemokine System in Experimental and Clinical Hematology

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 341))

Abstract

Acute graft vs. host disease (aGVHD) is a major limitation of hematopoietic stem cell transplantation (HSCT), and it causes significant morbidity and mortality for this patient population. This immune-mediated injury occurs unpredictably and is caused by donor-derived T cells reacting to recipient alloantigens. Although donor Th1 cells play a critical role in aGVHD generation, numerous arms of both the innate and the adaptive immune systems along with determinants of lymphocyte trafficking are likely involved in the multifaceted cascade of immunological events that culminates in clinical aGVHD. T regulatory and Th17 cells are T cell subsets distinct from Th1 cells that are likely involved with aGVHD. Regulatory T cells (Tregs) have been implicated in the prevention of aGVHD in both mouse and man, while Th17 cells may modulate early inflammatory responses associated with aGVHD, especially those involving the skin and the lungs. Interestingly, these two lymphocyte subsets appear to be reciprocally regulated in part through retinoic acid, through cytokines such as IL-6, and via interactions with dendritic cells. Another area under tight regulation appears to be the homing of lymphocytes to lymph nodes, skin, and gut. Adhesion molecules including chemokine receptors, selectins, and integrins may identify specific T cell subsets with unique migratory functional properties during HSCT. Controlling the migration patterns of Th17 cells and Tregs represents a potential therapeutic target. A major goal of HSCT research will be to develop approaches to pharmacologically manipulate T cell subsets in vivo or to select, expand, and infuse T cell subsets that will maximize the targeted graft vs. tumor effect while minimizing the potentially fatal side effects of aGVHD. A better understanding of Tregs and their tissue specificity should lead to improvement in the success of HSCT.

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Abbreviations

aGVHD:

Acute graft vs. host disease

ATG:

Antithymocyte globulin

ATRA:

All-trans-retinoic acid

CCL:

Chemokine ligand

CCRs:

Chemokine receptors

cGVHD:

Chronic graft vs. host disease

CLA:

Cutaneous lymphocyte antigen

CTLA4:

Cytotoxic T-lymphocyte associated antigen 4

E-selectin:

Endothelial-cell selectin

Foxp3:

Forkhead box protein P3

GITR:

Glucocorticoid tumor necrosis factor receptor

GVT:

Graft vs. tumor effect

HEVs:

High endothelial venules

HLA:

Human leukocyte antigen

HSCT:

Hematopoietic stem cell transplantation

IDO:

Indoleamine 2,3-dioxygenase

IL:

Interleukin

IPEX:

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

MADCAM1:

Mucosal vascular address in cell-adhesion molecule 1

MRD:

Matched related donor

P-selectin:

Platelet selectin

RIC:

Reduced intensity chemotherapy

ROR:

Retinoid-related orphan receptor

Tregs:

Regulatory T cells

URD:

Unrelated donor

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Acknowledgments

This work was supported by the National Institutes of Health/National Cancer Institute Grant K12 CA090625, the American Cancer Society–Institutional Research Grant (No. IRG-58-009-48) and the Sartain-Lanier Family Foundation. JEC is supported by a Burroughs Wellcome Clinical Scientist Award in Translational Research.

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Brian G. Engelhardt

  2. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    James E. Crowe Jr

  3. Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    James E. Crowe Jr

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  1. Brian G. Engelhardt
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  2. James E. Crowe Jr
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Correspondence to James E. Crowe Jr .

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Editors and Affiliations

  1. Dept. Medicine, Div. Infectious Diseases, Haukeland University Hospital, Bergen, 5021, Norway

    Oystein Bruserud

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Engelhardt, B.G., Crowe, J.E. (2010). Homing in on Acute Graft vs. Host Disease: Tissue-Specific T Regulatory and Th17 Cells. In: Bruserud, O. (eds) The Chemokine System in Experimental and Clinical Hematology. Current Topics in Microbiology and Immunology, vol 341. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_24

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