Interleukin-10 (IL-10) is a cytokine with a moleculary weight of 18 kDa, that was first identified as being produced by Th2 cells. It appears to have anti-inflammatory action by diminishing the production of pro-inflammatory cytokines produced by Th1 cells. IL-10 also regulates the differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells and granulocytes. Recent data suggest, however, that IL-10 also has immunostimulatory properties with important consequences on the prognosis of disease. In this study, we demonstrate the importance of injection of hematopoietic fetal liver cells transduced with the human IL-10 (hIL-10) gene into an allogenic recipient subsequently transplanted with allogenic skin grafts. The immaturity of stem cells and precursor cells from fetal liver and their transient survival in the host, due to the production of hIL-10, may afford 'prope' tolerance. It also explains the lack of graft-vs.-host reaction (GvHR) and the delay in rejection of the specific donor skin grafts after virtual disappearance of donor hematopoietic cells. Objectives: Transduction of CBA hematopoietic fetal cells with the human IL-10 gene was used with the aim of inducing tolerance to donor antigen in recipient BALB/c mice. The observed effects were prolonged IL-10 production, donor cell chimerism in the host and delayed rejection of skin grafts from the specific donor strain.
To prevent or delay rejection of highly incompatible skin allografts, we used IL-10 gene transfer to establish chimerism with donor hematopoietic cells. Fetal liver cells from CBA mice were transduced with the human IL-10 gene and injected into BALB/c mice.
Human IL-10, which is active in mice but does not cross-react with murine IL-10 in ELISA, was produced in vivo for 3 weeks. Donor cells were identified in the recipients during the same time period, on the basis of presence of the H-2 k gene and human IL-10 intracellular protein. Skin allografts from CBA or C57BL/6 mice survived for a mean of 9.5 days in recipient mice injected with non-transduced cells. In contrast, survival of CBA allograft was extended to 18.9+/-1.8 days in recipients injected with hIL-10-transduced fetal liver cells from CBA mice. Human IL-10 alone, without donor hematopoietic cell engraftment, did not prolong graft survival (9.6+/-1.2 days).
IL-10 transduction of donor hematopoietic stem cells resulted in production of IL-10, cell engraftment and chimerism. Although full tolerance was not obtained at this level of donor cell development in the host, a specific and highly significant (P<0.001) prolongation of the survival of donor skin allografts was observed.
[Show abstract][Hide abstract] ABSTRACT: The design of efficient parallel processing implementations for
speeding up the computationally intensive estimation of higher order
statistics (HOS) has been recognized as an important task by the signal
processing community. We report on the synthesis of minimum running time
(latency) data-parallel algorithms that can be employed to compute all
moment lags, up to the 3rd or 4th-order, on the MasPar-1 single
instruction multiple data (SIMD) parallel system. By construction the
synthesized SIMD algorithms require constant memory per processing
element (PE), thus allowing the processing of 1-D input data sequences
with as many as M=2<sup>10</sup> data samples. Simulation results are
presented showing the gain in speedup and execution times, as compared
to optimized versions of the serial estimation algorithm running in
Acoustics, Speech, and Signal Processing, 1995. ICASSP-95., 1995 International Conference on; 06/1995
[Show abstract][Hide abstract] ABSTRACT: Interleukin (IL)-10 regulates immune responses, acting as a suppressive cytokine by inhibiting the synthesis of Th1 cytokines, such as IL-2 and interferon (IFN)-gamma. It also strongly down-regulates major histocompatibility complex (MHC) class II determinants on antigen presenting cells (APC). On the other hand, long-term tolerance is well correlated with the persistence of a peripheral microchimerism. In this study, we investigated the synergistic effect of human IL-10 (huIL-10) and hematopoietic microchimerism for the induction of long-term tolerance. Irradiated Balb/c mice (H-2d) were used as recipients (fetal liver stem cells [FLSC], skin and heart) and C57BL/6 (H-2b) mice were used as donors of FLSC, skin and heart. Recipients were simultaneously transplanted with the heart, the skin and with huIL-10 gene-transduced FLSC. Microchimerism was checked using fluorescent flow cytometry, huIL10 production using enzyme-linked immunosorbent assay (ELISA), and graft survival was evaluated by daily observation. Significant level of huIL10 (up to 900 pg/mL) was detected for more than 2 weeks in the serum of mice that underwent transplantation. Four weeks after the FLSC injection, microchimerism was identified in the recipient lymphoid organs (spleen, thymus, and bone marrow) by the presence of donor cells (H-2b). Finally, in the group of mice treated with huIL-10 gene-transduced FLSC, skin allografts survived for 18.9 +/- 1.8 days compared with 9.5 and 9.6 days in the groups of mice treated with nontransduced FLSC or huIL-10 alone, respectively. The same pattern for heart allograft survival was observed. HuIL-10 transduction of donor hematopoietic stem cells resulted in production of huIL-10, cell engraftment, and chimerism. Although full tolerance was not obtained, specific and highly significant (P < .001) prolongation of the survival of donor heart allografts with (more than 2-fold compared with nontreated groups) was observed. The infiltration of the transplanted heart and its late rejection demonstrate that stem cells transduced with huIL-10 gene induce "prope" tolerance in this model.
[Show abstract][Hide abstract] ABSTRACT: Human interleukin 10 (hIL-10) may reduce acute rejection after organ transplantation. Our previous data shows that electroporation-mediated transfer of plasmid DNA to peripheral muscle enhances gene transduction dramatically. This study was designed to investigate the effect of electroporation-mediated overexpression of hIL-10 on acute rejection of cardiac allografts in the rat.
The study was designed to evaluate the effect of hIL-10 gene transfer on (a) early rejection pattern and (b) graft survival. Gene transfer was achieved by intramuscular (i.m.) injection into the tibialis anterior muscle of Fischer (F344) male recipients followed by electroporation 24 h prior to transplantation. Heterotopic cardiac transplantation was performed from male Brown Norway rat to F344. Four groups were studied (n = 6). Treated animals in groups B1 and B2 received 2.5 microg of pCIK hIL-10 and control animals in groups A1 and A2 distilled water. Graft function was assessed by daily palpation. Animals from group A1 were sacrificed at the cessation of the heart beat of the graft and those in group B1 were sacrificed at day 7; blood was taken for ELISA measurement of hIL-10 and tissue for myeloperoxidase (MPO) measurement and histological assessment. To evaluate graft survival, groups A2 and B2 were sacrificed at cessation of the heart beat of the graft.
Histological examination revealed severe rejection (IIIB-IV) in group A1 in contrast to low to moderate rejection (IA-IIIA) in group B1 (p = 0.02). MPO activity was significantly lower in group B1 compared to group A1 (18 +/- 7 vs. 32 +/- 14 mU/mg protein, p = 0.05). Serum hIL-10 levels were 46 +/- 13 pg/ml in group B1 vs. 0 pg/ml in group A1. At day 7 all heart allografts in the treated groups B1 and B2 were beating, whereas they stopped beating at 5 +/- 2 days in groups A1 and A2 vs. 14 +/- 2 days in group B2 (p = 0.0012).
Electroporation-mediated intramuscular overexpression of hIL-10 reduces acute rejection and improves survival of heterotopic heart allografts in rats. This study demonstrates that peripheral overexpression of specific genes in skeletal muscle may reduce acute rejection after whole organ transplantation.
The Journal of Gene Medicine 02/2006; 8(2):242-8. DOI:10.1002/jgm.859 · 2.47 Impact Factor
Franziska S. Hoffmann, Johann Hofereiter, Heike Rübsamen, Johannes Melms, Sigrid Schwarz, Hans Faber, Peter Weber, Benno Pütz, Verena Loleit, Frank Weber, Reinhard Hohlfeld, Edgar Meinl, Markus Krumbholz
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