Alemtuzumab as Antirejection Therapy: T Cell Repopulation and Cytokine Responsiveness.

T cell depleting antibody therapy is the treatment of choice for severe or glucocorticoid-resistant kidney transplant rejection.1 The most commonly used T cell depleting agent is rabbit antithymocyte globulin (rATG), but in recent years, the use of alemtuzumab to treat rejection has gained popularity.2-6 Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells. Ligation of alemtuzumab with CD52 induces apoptosis and lysis of immune cells through antibody- and complement-dependent cytotoxicity, which leads to profound and long-lasting lymphocyte depletion. Studies in kidney transplant patients given alemtuzumab as induction therapy have shown that low T cell numbers persisted for more than 1 year and that CD8+ T cells reach baseline levels earlier than CD4+ T cells.7 After T cell depletion therapy, T cell repopulation results from 2 processes: (i) thymopoiesis, the formation of new, naive T cells called recent thymic emigrants and (ii) homeostatic proliferation, the expansion of residual naive but mainly memory T cells. Naive recent thymic emigrant can be identified by the expression of CD31, which is lost on antigen binding and proliferation of the naive cell.8,9 Homeostatic proliferation of both naive and memory cells is the result of antigen binding to the T cell receptor and/or binding of the signal transducer and activator of transcription (STAT5) activating cytokines IL-7 and IL-15 to their cytokine receptor.9-13 As thymopoiesis decreases with age, homeostatic proliferation is the main contributor to T cell reconstitution in T cell–depleted adults. Furthermore, memory cells are relatively resistant to depletion and proliferating naive cells can also adapt a memory phenotype, resulting in a T cell pool which mainly comprises memory T cells after T cell depletion therapy.6,14-17 In addition to higher numbers of memory cells, higher percentages of regulatory T (Treg) cells have also been found after T cell depletion therapy.18-20 Homeostatic proliferation, in an activated immune environment, that is, high level IL-2 might play a role in the induction of Treg cells.19,21 Memory T cells can rapidly and vigorously respond to donor antigen, a response difficult to inhibit by immunosuppressive drugs. Therefore, memory cells are thought to endanger transplant survival.22,23 However, several studies reported that patients treated with T cell depletion therapy can be treated with reduced doses of maintenance immunosuppression, suggesting reduced immune functions of the repopulated T cells.24-28 In vitro, this impaired T cell function is reflected by hampered T cell responses to donor, third-party and recall antigens.7,16,20,29 Furthermore, after T cell depletion, T cells showed diminished homeostatic proliferation despite incomplete T cell reconstitution, and the phosphorylation capacity of STAT5 of recovered cells in response to IL-2 and IL-7 is affected.9,30 These recovered T cells also have increased expression of coinhibitory molecules.30 Impaired STAT signaling as well as increased expression of coinhibitory molecules are features of T cell exhaustion, a phenomenon induced by persistent antigen exposure resulting in dysfunctional T cells that is thought to contribute to donor hyporesponsiveness after kidney transplantation.30,31 During rejection, the immune system is highly activated, resulting in high concentrations of cytokines and antigen presentation, processes capable of influencing T cell reconstitution and function of the T cell pool by affecting the formation of Treg and the induction of T cell exhaustion. We therefore speculated that after alemtuzumab antirejection therapy, T cell reconstitution and T cell functions are altered and impaired due to the activated environment. In the present study, we monitored the kinetics of T cell repopulation and their cytokine responsiveness in kidney transplant patients before and after T cell depletion therapy during rejection.