High dose of antithrombin III induces indefinite survival of fully allogeneic cardiac grafts and generates regulatory cells.

Department of Surgery, Nihon University, Tokyo, Japan.
Transplantation (Impact Factor: 3.78). 01/2003; 75(2):217-20. DOI: 10.1097/01.TP.0000041781.94679.A1
Source: PubMed

ABSTRACT The authors investigated whether antithrombin III (AT-III) could induce unresponsiveness to alloantigens.
CBA mice were given intravenous injection of 50 or 500 U/kg AT-III or control plasma the same day as transplantation of a heart from a C57BL/6 mouse. An adoptive transfer study and mixed leukocyte culture analysis were also performed.
Naive CBA mice rejected C57BL/6 cardiac grafts acutely (median survival time [MST], 9 days). The 50-U/kg dose of AT-III induced a moderate increase in graft survival (MST, 25 days), whereas control mice rejected their graft acutely (MST, 7 days). With the 500-U/kg dose of AT-III, all grafts survived indefinitely (>100 days) and regulatory cells were generated. In vitro, AT-III suppressed proliferation of mixed leukocyte responses and generation of interleukin-2.
AT-III can be not only an antithrombotic agent but also a strong immunomodulating agent when used at high dose.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interactions between the immune response and brain functions such as olfactory, auditory, and visual sensations are likely. This study investigated the effect of sounds on alloimmune responses in a murine model of cardiac allograft transplantation. Naïve CBA mice (H2k) underwent transplantation of a C57BL/6 (B6, H2b) heart and were exposed to one of three types of music--opera (La Traviata), classical (Mozart), and New Age (Enya)--or one of six different single sound frequencies, for 7 days. Additionally, we prepared two groups of CBA recipients with tympanic membrane perforation exposed to opera for 7 days and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment). An adoptive transfer study was performed to determine whether regulatory cells were generated in allograft recipients. Immunohistochemical, cell-proliferation, cytokine, and flow cytometry assessments were also performed. CBA recipients of a B6 cardiac graft that were exposed to opera music and Mozart had significantly prolonged allograft survival (median survival times [MSTs], 26.5 and 20 days, respectively), whereas those exposed to a single sound frequency (100, 500, 1000, 5000, 10,000, or 20,000 Hz) or Enya did not (MSTs, 7.5, 8, 9, 8, 7.5, 8.5 and 11 days, respectively). Untreated, CBA mice with tympanic membrane perforations and CBA recipients exposed to opera for 7 days before transplantation (pre-treatment) rejected B6 cardiac grafts acutely (MSTs, 7, 8 and 8 days, respectively). Adoptive transfer of whole splenocytes, CD4+ cells, or CD4+CD25+ cells from opera-exposed primary allograft recipients resulted in significantly prolonged allograft survival in naive secondary recipients (MSTs, 36, 68, and > 100 days, respectively). Proliferation of splenocytes, interleukin (IL)-2 and interferon (IFN)-γ production was suppressed in opera-exposed mice, and production of IL-4 and IL-10 from opera-exposed transplant recipients increased compared to that from splenocytes of untreated recipients. Flow cytometry studies showed an increased CD4+CD25+ Forkhead box P3 (Foxp3)+ cell population in splenocytes from those mice. Our findings indicate that exposure to opera music, such as La traviata, could affect such aspects of the peripheral immune response as generation of regulatory CD4+CD25+ cells and up-regulation of anti-inflammatory cytokines, resulting in prolonged allograft survival.
    Journal of Cardiothoracic Surgery 03/2012; 7:26. · 0.90 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Herbal medicines have unique odors, and the act of smelling may have modulatory effects on the immune system. We investigated the effect of olfactory exposure to Tokishakuyaku-san (TJ-23), a Japanese herbal medicine, on alloimmune responses in a murine model of cardiac allograft transplantation.
    Journal of Cardiothoracic Surgery 05/2014; 9(1):82. · 0.90 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The co-inhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmunity and may potentially play an important role in allograft tolerance. This study investigated the effect of an agonistic anti-BTLA mAb (3C10) in the fully major histocompatibility complex-mismatched murine cardiac transplantation. CBA mice underwent transplantation of C57BL/6 hearts and received one dose of 3C10 on the day of transplantation (day 0) or four doses of 3C10 on day 0, 3, 6, and 9. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Moreover, to confirm the requirement for regulatory T cell and Th-2 cytokines, anti-interleukin (IL)-2 receptor alpha antibody (PC-61) or anti-IL-10 antibody (JES-2A5) was administered to a 3C10-treated CBA recipient. CBA mice treated with one and four doses of 3C10 prolonged allograft survival (median survival times [MSTs], 43 and >100 days, respectively). Secondary CBA recipients given whole splenocytes or CD4 cells from primary 3C10-treated CBA recipients had significantly prolonged survival of C57BL/6 hearts (MSTs, >100 in both). Also, flow cytometry studies showed an increased CD4CD25Foxp3 cell population in 3C10-treated mice. Additionally, IL-2 and interferon-γ production were suppressed in 3C10-treated mice, and IL-4 and IL-10 from 3C10-treated CBA mice increased. Moreover, 3C10 directly suppressed alloproliferation in a mixed leukocyte culture. However, administration of PC-61 or JES-2A5 clearly attenuated prolonged survival of 3C10-treated mice (MSTs, 15.5 and 13.5 days, respectively). 3C10 could control acute rejection by its suppressive effect on alloreactive T cells and induction of IL-10-dependent regulatory CD4 T cells.
    Transplantation 01/2014; · 3.78 Impact Factor