Homeostatic expansion as a barrier to lymphocyte depletion strategies

Abstract

Introduction Purpose of review Following lymphodepletion, lymphocytes repopulate the immune space both through enhanced thymopoiesis and proliferation of residual non-depleted 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 (IL-7) and Interleukin-15 (IL-15) regulate this process. Recent studies have also explored the functions of non-cytokine and signaling molecules in lymphopnenia-induced proliferation. Finally, we have seen the promise and limitations of several therapeutic approaches, including recombinant IL-7 therapy, CD8+-targeted antibodies, and peri-transplant cyclophosphamide, to treat post-transplant 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.

Cytomegalovirus-Responsive CD8+ T Cells Expand After Solid Organ Transplantation in the Absence of CMV Disease

“…Published research demonstrates that CMV specific T cells can cross‐react with alloantigen . In addition, memory T cells are resistant to lymphodepletion , which can lead to increased levels of alloreactive memory T cells . Therefore, a population of CMV‐responsive T cells could contain alloreactive cells that expand in response to donor alloantigen.…”

“…Therefore, homeostatic expansion does not enlarge the CD8 + T cell niche, and any changes are within the preexisting niche. Specifically, immunosuppression and lymphodepletion can cause expansion of memory and effector T cells at the expense of other T cell populations . We assessed the potential effects of lymphodepletion through comparison of CMV‐responsive CD8 + T cells in transplant recipients with and without lymphodepleting induction therapy.…”

Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients

“…The monkeys were also given anti–interleukin‐6 receptor (IL‐6R) monoclonal antibody (Ab) [to antagonize potential inhibitory/destabilizing effects of IL‐6 on Treg function ] and rapamycin. These agents were administered in an effort to promote/augment Treg survival/function in the early postsurgical period (up to 1 month posttransplantation) before homeostatic recovery of effector/memory cells , when host T cells were profoundly depleted.…”

The effect of anti‐thymocyte globulin and everolimus on the kinetics of cytomegalovirus viral load in seropositive kidney transplant recipients without prophylaxis

“…21 The use of rATG is associated with reduced incidence of early T cell mediated acute rejection but following the period of lymphodepletion, proliferation of residual non-depleted peripheral lymphocytes repopulates toward allospecific, effector-memory phenotypes. 22,23 Combined use of mTOR inhibitors may attenuate the generation of allospecific effector-memory T cells and increase the relative proportion of Treg following depletional therapy. 6 The early and steep but transient increase in the proportion of patients with CMV viral load despite lowest incidence of CMV infection/disease in the rATG/EVR group is intriguing.…”