Single-dose safety and pharmacokinetics of ST-246, a novel orthopoxvirus egress inhibitor.

ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers.

Modification of monoclonal antibody carbohydrates by oxidation, conjugation, or deoxymannojirimycin does not interfere with antibody effector functions.

Site-specific attachment of metal chelators or cytotoxic agents to the carbohydrate region of monoclonal antibodies results in clinically useful immunoconjugates [Doerr et al. (1991) Ann Surg 214: 118, Wynant et al. (1991) Prostate 18: 229].

Failure of in vitro assays to predict accurately the existence of neonatally induced H-2 tolerance.

Tolerogen-specific alloreactivity, in the form of mixed lymphocyte responses and cell mediated lympholysis, was measured in vitro using lymphocytes from mice that received neonatal inoculations of H-2 semiallogeneic hematopoietic cells. It was found that depletion of specific alloreactivity, as detected by these assays, was discernable within the thymus glands within 24 to 48 hr of injection. Reduced in vitro alloreactivity was also apparent among spleen cells obtained from neonatally injected mice that had matured immunologically (8 weeks of life).

Characterization of cytotoxic cells in mice rendered neonatally tolerant of MHC alloantigens: evidence for repertoire modification.

A common prediction of clonal deletion/inactivation hypotheses is that cells with high avidity for tolerogen are preferentially eliminated, with low avidity cells being most likely to escape the tolerance induction mechanism. Thus it would be expected that the tolerogen-specific cells in tolerant mice would have a different repertoire than those in normal mice. To find evidence in favor of this prediction, neonatal B10.

Allo-I-J determinants participate in maintenance of neonatal H-2 tolerance.

To evaluate the role of IJ antigens in maintenance of the tolerant state in adult H-2 tolerant mice, we have attempted to abolish tolerance by injecting monoclonal antibodies (mab) specific for host, donor, or third party IJ antigens into adult H-2 tolerant mice. Abolition of tolerance was evidenced by the rejection of fresh test skin grafts bearing the tolerated antigens. Whole H-2 tolerant mice treated with anti-IJ mab specific for donor (allo) IJ antigens rejected their test skin grafts, indicating that tolerance had been abolished.

Clonal analysis of helper and effector T-cell function in neonatal transplantation tolerance: clonal deletion of helper cells determines lack of in vitro responsiveness.

Mice rendered tolerant at birth of H-2 alloantigens display concordant in vivo and in vitro phenotypes: they fail to reject skin grafts bearing the tolerated antigens, and their lymphoid cells fail to participate in tolerogenspecific mixed lymphocyte reactions (MLRs) and cell-mediated lympholysis (CML). Tolerant animals normally reject third-party skin allografts and develop positive MLRs and CML to third-party antigens. It has been suggested that clonal deletion of antigen reactive cells is the basis for this spectrum of responses.

Analysis of neonatally induced tolerance of H-2 alloantigens. III. Ease of abolition of tolerance of class I, but not class II, antigens with infusions of syngeneic, immunocompetent cells.

Neonatally-induced tolerance of class I H-2 alloantigens can be abolished in adult, long-term-tolerant mice by infusions of immunocompetent cells from donors syngeneic with the recipient. By contrast, neonatally-induced tolerance of Ia alloantigens can not be abolished easily, indicating that the Ia-specific tolerant state is maintained by an active process that can be impressed upon mature alloreactive lymphoid cells in the tolerant environment. This finding is concordant with previous observations that tolerance of Ia alloantigens can readily be transferred adoptively by inoculating lymphoid cells from tolerant mice into syngeneic, naive recipients.

Analysis of neonatally induced tolerance of H-2 alloantigens. IV. Graft adaptation in long-term tolerated grafts.

Acceptance of orthotopic test skin grafts bearing putative tolerogenic H-2 determinants proves to be the most stringent criterion for the existence of neonatally induced transplantation tolerance. The large majority of long-standing grafts retain their original antigenicity--that is, they are rejected when tolerance is abolished by infusions of immunocompetent cells syngeneic with the tolerant host; and they remain immunogenic--that is, they induce their own rejection when excised and placed on naive recipients syngeneic with the tolerant animal. However, the ability of these long-standing grafts to reflect concordantly the alloreactive potential of peripheral lymphoid cells of tolerant mice deteriorates in time.