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Homeostatic expansion as a barrier to lymphocyte depletion strategies

Zwang, Nicholas A.a; Turka, Laurence A.b

Current Opinion in Organ Transplantation: August 2014 - Volume 19 - Issue 4 - p 357–362
doi: 10.1097/MOT.0000000000000096
TOLERANCE INDUCTION: Edited by Herman Waldmann

Purpose of review Following lymphodepletion, lymphocytes repopulate the immune space both through enhanced thymopoiesis and proliferation of residual nondepleted peripheral lymphocytes. The term homeostatic proliferation (alternatively homeostatic expansion or lymphopenia-induced proliferation) refers to the latter process. Homeostatic proliferation is especially relevant to reconstitution of the lymphocyte compartment following immunodepletion therapy in transplantation. Repopulating lymphocytes can skew toward an effector memory type capable of inducing graft rejection, autoimmunity, or, in the case of allogeneic bone marrow transplantation, graft versus host disease. Here we review recent studies exploring the biologic mechanisms underlying homeostatic proliferation and explore implications for therapy in transplantation.

Recent findings Two immune-depleting agents, alemtuzumab and rabbit antithymocyte globulin, have been well characterized in their abilities to induce an effector-memory phenotype in repopulating lymphocytes. Additionally, we have gained new understandings of the mechanisms by which the cytokines interleukin-7 and interleukin-15 regulate this process. Recent studies have also explored the functions of noncytokine and signaling molecules in lymphopenia-induced proliferation. Finally, we have seen the promise and limitations of several therapeutic approaches, including recombinant interleukin-7 therapy, CD8+-targeted antibodies, and peri-transplant cyclophosphamide, to treat posttransplant lymphopenia and reduce the risks of immune dysregulation following homeostatic proliferation.

Summary Immune dysfunction following homeostatic proliferation is a special challenge in transplantation. A deeper understanding of the underlying biology has led to a number of promising new therapies to overcome this problem.

aDepartment of Medicine

bDepartment of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

Correspondence to Laurence A. Turka, Transplantation Biology Research Center MGH-East, Bldg. 149-9019, 13th Street, Boston, Massachusetts 02129, USA. Tel: +1 617 724 7740; fax: +1 617 726 6925; e-mail:

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins