Enhanced Immune System Regeneration in Humans Following Allogeneic or Autologous Hemopoietic Stem Cell Transplantation by Temporary Sex Steroid Blockade

Abstract

Purpose: To determine if temporarily blocking sex steroids prior to stem cell transplantation can increase thymus function and thus enhance the rate of Tcell regeneration. Experimental Design: This was a pilot study of luteinizing hormone^releasing hormone agonist (LHRH-A) goserelin given 3 weeks prior to allogeneic or autologous hemopoietic stem cell transplantation and administered up to 3 months posttransplantation. Patients (with or without LHRH-A administration) were assessed from 1week to 12 months posttransplantation for multiple immunologic variables by flow cytometry (particularly naI« ve T cells), quantitative PCR to assess T-cell receptor excision circle levels (as a correlate of thymus function), CDR3 length analysis to determine the variability of the TCR repertoire, and in vitro assays to determine functional T cell responses. Results: LHRH-A administration prior to stem cell transplantation significantly increased neutrophil and lymphocyte numbers within the first month of posttransplantation. Most importantly, total and naI« ve CD4 + T cell regeneration together with T-cell receptor excision circle production, T cell repertoire regeneration, and peripheral T cell function were also significantly enhanced at multiple time points posttransplant. In addition, an increase in disease-free survival (P = 0.04) was seen in the autologous setting. Although LHRH-A administration increased T cell responses in vitro, it did not exacerbate graft-versus-host disease in the allogeneic setting. Conclusions: This study provides an important new approach to the improvement of immune reconstitution in patients undergoing hemopoietic stem cell transplantation and may have generic applications in manyTcell^based disorders.

T-cell reconstitution after allogeneic stem cell transplantation: assessment by measurement of the sjTREC/ TREC ratio and thymic naive T cells

“…If confirmed, this observation would have potential therapeutic consequences given that treatment with keratinocyte growth factor (KGF, Palifermin) and/or androgen blockade might protect the vulnerable thymic epithelial cells against damage and or accelerate their recovery. 33,35 The first clinical trials testing this hypothesis are ongoing, 36 and our method of measuring the TF might be helpful in monitoring the response to therapy. Approximately 50% of patients showed quite a different pattern of recovery with an almost complete lack of βTREC being the major defect (group B).…”

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

“…Since immunity can be restored faster following chemotherapy and hemopoietic stem cell transplantation, using reversible sex steroid blockade (52,(75)(76)(77)(78), hemopoietic stem cell transplantation may be rendered safe enough to reinstate tolerance in some autoimmunity patients given a similar though less myeloablative regime. However, any underlying stromal defects must be considered, as their effects could be magnified following thymic hypertrophy, increasing the risk of relapse, particularly if stromal cells are incapable of expansion.…”

Neuro-endocrine-immune Crosstalk and Implications for Cancer Therapy

“…The increased thymic cellularity involved all of the thymocyte subsets and early T lineage progenitors; in addition, surgical castration seems to induce early repair of damaged thymic stromal microenvironment resulting in enhanced production of chemokines and growth factors important for thymopoiesis [99]. Importantly, these observations have also been demonstrated in the clinical HSCT setting, where treatment with goserelin (an LHRH agonist) prior to HSCT resulting in improved thymopoiesis and disease-free survival without an increase in GVHD post-HSCT [102]. These results are encouraging and support further investigation into modulation of thymic function and immune responses using endocrine-based therapies.…”