Comprehensive Review
Lymphodepletion and Homeostatic Proliferation: Implications for Transplantation

https://doi.org/10.1111/j.1600-6143.2012.04008.xGet rights and content
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Control of the alloimmune response requires elimination and/or suppression of alloreactive immune cells. Lymphodepleting induction therapies are increasingly used to accomplish this goal, both as part of tolerance induction protocols or to reduce the requirements for maintenance immunosuppression in the peritransplant setting. However, it is well recognized that lymphopenia induces compensatory proliferation of immune cells, generally termed “homeostatic proliferation,” which favors the emergence of memory T cells. Paradoxically therefore, the result may be a situation that favors graft rejection and/or makes tolerance difficult to achieve or sustain. Yet all depletion is not alike, particularly with respect to the timing of reconstitution and the types of cells that repopulate the host. Thus, to design more effective induction strategies it is important to understand the homeostatic mechanisms, which exist to maintain a balanced repertoire of naïve and memory T and B cells in the periphery and how they respond to lymphodepletion. Here we will review the biology of homeostatic proliferation stimulated by lymphopenia, the effects of specific depleting agents on reconstitution of the T- and B-cell immune repertoire, drawing from both from animal models and human experience, and potential strategies to enhance allodepletion while minimizing the adverse effects of homeostatic proliferation.

Key words:

T cell
memory
tolerance

Abbreviations:

APC
antigen presenting cell
APRIL
a proliferation inducing ligand
ATG
antithymocyte globulin
BAFF
B-cell activating factor, TNF family
BCMA
B-cell maturation
BCR
B-cell receptor
BLyS
B lymphocyte stimulator
BR3
B-cell–activating factor receptor 3
CNI
calcineurin inhibitor
CTL
cytotoxic lymphocyte
DSA
donor specific antibody
FO
follicular
FoxP3
forkhead box P3
HAART
highly active antiretroviral therapy
HIV
human immunodeficiency virus
HP
homeostatic proliferation
IFN gamma
interferon gamma
IL-7R
interleukin 7 receptor
ITP
idiopathic thrombocytopenic purpura
MHC
major histocompatibility complex
MZ
marginal zone
RAG-/-
recombinase activating gene deficient
rATG
rabbit antithymocyte globulin
SCID
severe combined immunodeficiency
SLO
secondary lymphoid organ
TACI
transmembrane activator and calcium-modulating cyclophilin ligand interactor
TCR
T-cell receptor
TNFR
tumor necrosis factor receptor
TREC
T-cell receptor excision circles

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