Kinetics of Homeostatic Proliferation and Thymopoiesis after rATG Induction Therapy in Kidney Transplant Patients

Bouvy, Anne P.; Kho, Marcia M. L.; Klepper, Mariska; Litjens, Nicolle H.R.; Betjes, Michiel G. H.; Weimar, Willem; Baan, Carla C.

doi:10.1097/tp.0b013e3182a203e4

Cited by 38 publications

(45 citation statements)

References 36 publications

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“…Recent examination of the kinetics of lymphocyte depletion following rATG given as induction therapy in renal transplantation found that rATG durably depletes the T cell compartment to counts below 250 CD3 + cells/uL at six months, compared to minimal T cell depletion following basiliximab or no induction therapy. 19 In contrast to prior studies, this recent investigation found no increase in thymopoiesis ( i.e., CD31 + cells among CD4 + or CD8 + cells) one month following rATG induction. Rather, peripheral cytokine-mediated signaling by IL-7 and IL-15 via Stat5 increased in the first month following rATG therapy, particularly among memory T cell subsets.…”

Section: Pharmacologic Lymphocyte Depletion Promotes Autoimmunitycontrasting

confidence: 80%

Homeostatic expansion as a barrier to lymphocyte depletion strategies

Zwang

Turka²

2014

Current Opinion in Organ Transplantation

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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.

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Section: Pharmacologic Lymphocyte Depletion Promotes Autoimmunitycontrasting

confidence: 80%

Homeostatic expansion as a barrier to lymphocyte depletion strategies

Zwang

Turka²

2014

Current Opinion in Organ Transplantation

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“…Gurkan et al (14) reported evidence for both thymopoiesis and homeostatic proliferation contributing to immune reconstitution after rATG. More recently, Bouvy et al (15) measured the percentage of RTE at 1, 3, and 6 months after rATG and showed no effect of rATG on thymopoiesis. Several differences with our study are noteworthy.…”

Section: Discussionmentioning

confidence: 99%

“…Several differences with our study are noteworthy. The first study (14) included pediatric patients in whom thymopoiesis could be preserved; the number of patients in Bouvy et al's (15) report was limited (8 ATG and 8 basiliximab) hampering the relevance of their findings; finally, both studies (14,15) explored thymic output during the first 6 months while we studied thymic function one year after transplantation. Hence, a thymic toxicity of ATG remains controversial.…”

Section: Discussionmentioning

confidence: 99%

ATG-Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

Crépin

Carron

Roubiou

et al. 2015

American Journal of Transplantation

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y These authors contributed equally to this work. Persistent ATG-induced CD4þ T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR À62 patients receiving ATG and 35 receiving anti-CD25 mAb (a-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34 þ hematopoietic progenitor cells (CD34 þ HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased oneyear posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57 þ /CD28 À T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4 þ T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection.

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“…The absolute numbers of the different T cell subsets were determined via Trucount staining (Becton Dickinson, Franklin Lakes, NJ), as described by Bouvy et al (22).…”

Section: T Cell Differentiation Status and Absolute Numbers Of T Cellmentioning

confidence: 99%

Uremia-Associated Premature Aging of T Cells Does Not Predict Infectious Complications After Renal Transplantation

Dedeoğlu

Meijers

Klepper

et al. 2016

American Journal of Transplantation

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Patients with end-stage renal disease have prematurely aged T cell systems. We tested whether T cell aging parameters were associated with the risk of infections after renal transplantation (RTx). We studied 188 patients over 1 year. Peripheral T cells were analyzed before and at 3 and 6 mo after RTx for frequency of recent thymic emigrants, relative telomere length and differentiation status. These parameters were related to the occurrence of opportunistic and serious infections. Overall, 84 patients developed an infection. In this group, 50 developed an opportunistic infection and 53 developed a serious infection. T cell aging parameters assessed before RTx were not associated with infection risk. The memory T cells showed a decrease within the first 3 mo in both groups (p < 0.001). The CD4 + memory T cells increased between 3 and 6 mo within the infection group (p = 0.015). The number of CD8 + memory T cells increased in both groups (p < 0.001) but reached baseline levels only in the infection group. In the infection group, the CD8 + CD28null T cell percentage increased between 3 and 6 mo (p = 0.024), tending to be higher than at baseline (p = 0.061). These differences in post-RTx dynamics resulted from infections. Parameters of uremia-associated premature aging of peripheral T cells do not predict posttransplant infections.

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Kinetics of Homeostatic Proliferation and Thymopoiesis after rATG Induction Therapy in Kidney Transplant Patients

Cited by 38 publications

References 36 publications

Homeostatic expansion as a barrier to lymphocyte depletion strategies

Homeostatic expansion as a barrier to lymphocyte depletion strategies

ATG-Induced Accelerated Immune Senescence: Clinical Implications in Renal Transplant Recipients

Uremia-Associated Premature Aging of T Cells Does Not Predict Infectious Complications After Renal Transplantation

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