The effect of CD28/B7 blockade on alloreactive T and B cells after liver cell transplantation.

BACKGROUND: Hepatocyte cell lines are beginning to be developed as universal donors for isolated liver cell transplantation, which is a less invasive method than orthotopic liver transplantation for treatment of metabolic liver disease. The immune response to isolated liver cell transplantation and its modification by costimulatory blockade are as yet not well delineated. METHODS: Adenovirus expressing CTLA4Ig was used to study blockade of the costimulatory CD28/B7 pathway in murine models of hepatocyte transplantation, and the effects on alloreactive T and B cells were studied. RESULTS: CTLA4Ig delayed rejection of subcutaneously administered C57L-derived murine hepatoma cells in CBA/J recipients for >50 days. Activation and cytokine secretion by allospecific CD4+ and CD8+ T cells were initially blocked by CTLA4Ig; delayed rejection was associated with tumor infiltration by CD8+ T cells that did not secrete interferon-gamma. CTLA4Ig failed to block transplant rejection in primed mice, indicating that memory effector T cells were resistant to its action. In contrast, CTLA4Ig suppressed both naive and memory alloreactive B cells. High levels of CTLA4Ig mediated acceptance of hepatoma cells delivered directly into the spleen. However, isolated primary C57BL/6 mouse hepatocytes delivered into the spleen were rejected with only moderately delayed kinetics. CONCLUSIONS: Transplant antigenicity, transplant site, and CTLA4Ig dose all affected the survival of transplanted liver cells. CD8+ T cells are significant mediators of hepatocyte transplant rejection and are relatively resistant to costimulatory blockade with CTLA4Ig. Strategies to specifically antagonize CD8+ T cells or to modulate MHC class I expression in association with costimulatory blockade by CTLA4Ig may enhance the clinical feasibility of transplanting allogeneic hepatocytes.

A prospective comparison of three heat preservation methods for patients undergoing hypothermic cardiopulmonary bypass.

OBJECTIVE: To prospectively compare 3 methods of body heat preservation in patients undergoing surgery requiring the use of hypothermic cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, and nonblinded. SETTING: University teaching hospital. PARTICIPANTS: Adult cardiac surgery patients (n = 101). INTERVENTIONS: Subjects were randomly assigned to 1 of 3 treatment groups: Group 1 (n = 33) used a fluid-filled warming blanket, group 2 (n = 31) used a heated and humidified breathing circuit, and group 3 (n = 37) used intravenous fluid warmers for the administration of all fluids. Treatments started on separation from CPB and concluded at the end of the intraoperative experience. Anesthetic technique, minute ventilation, conduct of CPB, and room temperature in the operating room were standardized. MEASUREMENTS AND MAIN RESULTS: Blood temperature was measured at its nadir on CPB, on separation from CPB, and just before departure from the operating room. No differences were found among groups for CPB duration, coldest venous temperature on CPB, rewarming time, rate of rewarming, room temperature, or blood temperature on separation from CPB. There were no significant differences found in post-CPB temperature afterdrop among groups. CONCLUSIONS: This study suggests that there is no statistically significant disparity in the effectiveness of these 3 intraoperative heat preservation methods. Ease of use and cost-effectiveness should guide the choice of warming method post-CPB.

CTLA4Ig inhibits T cell-dependent B-cell maturation in murine systemic lupus erythematosus.

Long-term administration of CTLA4Ig prevents the onset of disease in systemic lupus erythematosus-prone (SLE-prone) NZB/NZW F1 mice. To determine the mechanism of this effect, we engineered an adenovirus that expresses murine CTLA4Ig. Administration of a single high dose of this virus results in long-term expression of CTLA4Ig in the serum and absence of an immune response to the adenoviral vector. We administered Ad-CTLA4Ig to 19- to 22-week-old NZB/NZW F1 mice and evaluated the effect on anti-DNA antibody-producing B cells. We show that CTLA4Ig has a beneficial effect on murine SLE for as long as it is present in the serum. This effect is associated with decreased expansion of both the IgM and IgG autoreactive B-cell population, inhibition of immunoglobulin class switching, decreased frequency and altered pattern of somatic mutation, and a marked decrease in the numbers of activated CD4-positive T cells. In contrast, intrinsic B-cell hyperreactivity and the survival of plasma cells in the bone marrow, both of which are less dependent on T-cell help, appear to be unaffected by CTLA4Ig. High-dose CTLA4Ig did not induce permanent tolerance in this autoimmune disease model. Furthermore, although the mice survived in a conventional housing facility, treatment with Ad-CTLA4Ig was immunosuppressive.