High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells.

Abstract

SttnaryTransplantation of HLA mismatched hematopoietic stem cells in patients with severe combined immunoddiciency (SCID) can result in a selective engraftment of T cells of donor origin with complete immunologic reconstitution and in vivo tolerance. The latter may occur in the absence of clonal deletion of donor T lymphocytes able to recognize the host HLA antigens. The activity of these host-reactive T cells is suppressed in vivo, since no graft-vs.-host disease is observed in these human chimeras. Here it is shown that the CD4 + host-reactive T cell clones isolated from a SCID patient transplanted with fetal liver stem cells produce unusually high quantities ofinterleukin 10 (IL-10) and very low amounts of IL-2 after antigen-specific stimulation in vitro. The specific proliferative responses of the host-reactive T cell clones were considerably enhanced in the presence of neutralizing concentrations of an anti-IL-10 monodonal antibody, suggesting that high levels of endogenous IL-10 suppress the activity of these cells. These in vitro data correlate with observations made in vivo. Semi-quantitative polymerase chain reaction analysis carried out on freshly isolated peripheral blood mononuclear cells (PBMC) of the patient indicated that the levels of IL-10 messenger KNA (mRNA) expression were strongly enhanced, whereas IL-2 mKNA expression was much lower than that in PBMC of healthy donors. In vivo IL-10 mRNA expression was not only high in the T cells, but also in the non-T cell fraction, indicating that host cells also contributed to the high levels of IL-10 in vivo. Patient-derived monocytes were found to be major IL-10 producers. Although no circulating IL-10 could be detected, freshly isolated monocytes of the patient showed a reduced expression of class II HLA antigens. However, their capacity to stimulate T cells of normal donors in primary mixed lymphocyte cultures was within the normal range. Interestingly, similar high in vivo IL-10 mKNA expressions in the T and non-T cell compartment were also observed in three SCID patients transplanted with fetal liver stem cells and in four SCID patients transplanted with T cell-depleted haploidentical bone marrow stem cells. Taken together, these data indicate that high endogenous IL-10 production is a general phenomenon in SCID patients in whom allogeneic stem cell transplantation results in immunologic reconstitution and induction of tolerance. Both donor T cells and host accessory cells contribute to these high levels of IL-10, which would suppress the activity of host-reactive T cell in vivo. GVHD remains the major clinical problem after allogeneic hematopoietic stem cell transplantation (1-3).

Dendritic Cells Pulsed with Fungal RNA Induce Protective Immunity toCandida albicansin Hematopoietic Transplantation

“…It is known that high levels of IL-10 are associated with tolerance to HLA-mismatched BM stem cells (52) and IL-10 is required for the induction of regulatory T cells mediating tolerance to alloantigens in vivo (52)(53)(54)(55). Different regulatory T cells have been reported and they are known to differentiate upon the encounter with immature DC (53,55).…”

Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses

“…on days 0, 1 and 2 after transplant with 800 g of the purified rat anti-human IL-10 mAb JES3-19F1.1.1 (American Type Culture Collection, Rockville, MD, USA) that neutralizes vIL-10 but does not cross-react with murine cellular IL-10. 48 Recovery of heart infiltrating cells Hearts were removed, minced and digested with 1 mg/ml collagenase A (Boehringer Mannheim Biochemicals, Indianapolis, IN, USA) for 30 min at 37°C. Heart infiltrating cells were washed free of collagenase and viable leukocytes enumerated by trypan blue exclusion.…”

Impaired regulatory T cell function in germ‐free mice

“…Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g.…”

“…Lack of a functional Foxp3 gene result in the severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by organ-specific autoimmunity, colitis and high IgE levels [10,11]. Mice with spontaneous or induced mutations in the Foxp3 gene that impair Foxp3 expression fail to develop CD4 + CD25 + Treg and exhibit a syndrome similar to IPEX [5,6].Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g.…”