ABSTRACT
The incidence of developing circulating anti-human leukocyte antigen antibodies and the kinetics of T cell depletion and recovery among pediatric renal transplant recipients who receive alemtuzumab induction therapy are unknown. In a collaborative endeavor to minimize maintenance immunosuppression in pediatric renal transplant recipients, we enrolled 35 participants from four centers and treated them with alemtuzumab induction therapy and a steroid-free, calcineurin-inhibitor-withdrawal maintenance regimen. At 3 months after transplant, there was greater depletion of CD4(+) than CD8(+) T cells within the total, naive, memory, and effector memory subsets, although depletion of the central memory subset was similar for CD4(+) and CD8(+) cells. Although CD8(+) T cells recovered faster than CD4(+) subsets overall, they failed to return to pretransplant levels by 24 months after transplant. There was no evidence for greater recovery of either CD4(+) or CD8(+) memory cells than naïve cells. Alemtuzumab relatively spared CD4(+)CD25(+)FoxP3(+) regulatory T cells, resulting in a rise in their numbers relative to total CD4(+) cells and a ratio that remained at least at pretransplant levels throughout the study period. Seven participants (20%) developed anti-human leukocyte antigen antibodies without adversely affecting allograft function or histology on 2-year biopsies. Long-term follow-up is underway to assess the potential benefits of this regimen in children.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Neoplasm/pharmacology , Antineoplastic Agents/pharmacology , HLA Antigens/immunology , Kidney Transplantation/immunology , T-Lymphocytes/drug effects , Adolescent , Alemtuzumab , Child , Female , Humans , Immunosuppression Therapy , Male , Prospective StudiesABSTRACT
Regulatory T cells (Tregs) migrate into peripheral sites of inflammation such as allografts undergoing rejection, where they serve to suppress the immune response. In this study, we find that â¼30-40% of human CD25(hi) FOXP3(+) CD4(+) Tregs express the peripheral CXC chemokine receptor 3 (CXCR3) and that this subset has potent immunoregulatory properties. Consistently, we observed that proliferative responses as well as IFN-γ production were significantly higher using CXCR3-depleted versus undepleted responders in the mixed lymphocyte reaction, as well as following mitogen-dependent activation of T cells. Using microfluidics, we also found that CXCR3 was functional on CXCR3(pos) Tregs, in as much as chemotaxis and directional persistence towards interferon-γ-inducible protein of 10 kDa (IP-10) was significantly greater for CXCR3(pos) than CXCR3(neg) Tregs. Following activation, CXCR3-expressing CD4(+) Tregs were maintained in vitro in cell culture in the presence of the mammalian target of rapamycin (mTOR) inhibitor rapamycin, and we detected higher numbers of circulating CXCR3(+) FOXP3(+) T cells in adult and pediatric recipients of renal transplants who were treated with mTOR-inhibitor immunosuppressive therapy. Collectively, these results demonstrate that the peripheral homing receptor CXCR3 is expressed on subset(s) of circulating human Tregs and suggest a role for CXCR3 in their recruitment into peripheral sites of inflammation.
Subject(s)
Forkhead Transcription Factors/immunology , Receptors, CXCR3/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Cell Movement/immunology , Cell Proliferation/drug effects , Cells, Cultured , Chemokine CXCL10/immunology , Chemokine CXCL10/metabolism , Child , Flow Cytometry , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression , Humans , Immunosuppressive Agents/pharmacology , Interferon-gamma/immunology , Interferon-gamma/metabolism , Kidney Transplantation , L-Selectin/genetics , L-Selectin/immunology , L-Selectin/metabolism , Lymphocyte Activation/immunology , Receptors, CCR4/genetics , Receptors, CCR4/immunology , Receptors, CCR4/metabolism , Receptors, CXCR3/genetics , Receptors, CXCR3/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sirolimus/pharmacology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/metabolismABSTRACT
Treatment and prevention of allograft loss in organ transplant recipients relies chiefly on non-antigen-specific immunosuppression. Current approaches to the management of these immunosuppressive drugs are largely empiric and reactive because of lack of immune monitoring assays. Alloreactive T cells play a key role in acute rejection and in development of chronic allograft nephropathy, the leading cause of late allograft failure. There is thus an increasing interest in development of simple, reliable, noninvasive assays measuring allogeneic anti-donor responsiveness or donor-specific nonresponsiveness to predict transplantation rejection and tolerance. Because the frequency and cytokine profile of alloreactive T cells play an important role in these processes, this article mainly focuses on assays that enumerate cytokine-producing alloreactive T cells.
