Cyclosporin A effects during primary and secondary activation of human umbilical cord blood T lymphocytes

Abstract

Thus, our studies do not support the previous hypothesis that reduced GVHD observed after UCB transplantation is attributable to increased CsA sensitivity of UCB T cells. Rather, reduced UCB T-cell cytokine production and increased AICD may be important cellular mechanisms underlying these favorable rates of GVHD in UCB transplant recipients.

Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation

“…We and others 12,13,23 have previously reported increased autoproliferation as well as increased proliferation of UCB cells after primary and secondary stimulation compared with AB cells. Additionally, we have reported increased AICD in UCB T cells after secondary stimulation.…”

“…While Th1 cytokine deficiency in UCB T cells has been well documented [7][8][9][10][11][12] and has been corroborated by this gene expression data, conflicting data exist regarding Th2 cytokine expression. 7,10,13,43,50-52 Several studies have described higher levels of Th2 cytokines in UCB than in adult, 50,52 suggesting a Th2 shift that may underlie reduced GVHD observed after UCB transplantation.…”

“…5,6 Potential cellular and molecular mechanisms that underlie the clinical observations of low rates of GVHD in UCB recipients have been investigated. It has been shown that activated UCB lymphocytes produce lower amounts of cytokines after primary and secondary stimulation compared with activated adult T lymphocytes, including interferon-␥ (IFN-␥) [7][8][9][10][11][12] and tumor necrosis factor-␣ (TNF-␣), 7,[10][11][12] which play an important role in clinical GVHD. Additionally, production of the cytokines interleukin-2 (IL-2) 7,9,10 and IL-4 7 by activated UCB T cells is reduced compared with the response observed in adult blood (AB) T cells.…”

“…Moreover, although UCB T lymphocytes proliferate at rates equivalent to adult T lymphocytes in response to primary stimulation, alloantigenspecific cytotoxicity is reduced in UCB T lymphocytes when compared with adult controls after secondary stimulation. [12][13][14] The NFAT (nuclear factor of activated T cells) family of transcription factors contains 5 distinct NFAT proteins: NFATc1 (NFAT2 or NFATc), NFATc2 (NFAT1 or NFATp), NFATc3 (NFAT4 or NFATx), NFATc4 (NFAT3), and NFAT5 (tonicity enhancer binding protein [TonEBP]). 15,16 NFATc1-NFATc4 proteins are defined by a common regulatory domain that is the target of calcineurin, a calcium/calmodulin-dependent protein phosphatase.…”

The 6-OHDA mouse model of Parkinson's disease – Terminal striatal lesions provide a superior measure of neuronal loss and replacement than median forebrain bundle lesions

“…Assessing the potential of mouse-derived ES cells to develop into functional dopamine neurons via transplantation into the 6-OHDA rat model of PD is, however, far from ideal since rats receiving the xenografts require immunosuppression to avoid graft rejection. This is normally achieved by the administration of the drug Cyclosporin A (CsA), which suppresses the immune response by inhibiting T-cell activation [30]. While CsA promotes xenograft survival [31], its use is problematic because not only is prevention from cell rejection not absolute [32] but also, CsA treatment is as -1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 13 sociated with toxic side effects such as hepatotoxicity or even death [33].…”