Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection

BACKGROUND: The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts. METHODS: We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes. RESULTS: None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection. CONCLUSIONS: These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.     

Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients

BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.     

Thymic function, aging, and AIDS

For the first time, physicians are challenged by clinical states in which the T-cell pool is destroyed postnatally in large numbers of patients. One such state is AIDS; another is the immune damage of cancer chemotherapy. Accordingly, study of postnatal thymic function is now a matter of clinical urgency. Ongoing work may point toward new strategies for repairing a damaged T-cell repertoire.     

The Subtle Points of Controversy: A Case Study in Implementing Sex Education

Although surveys have documented the ignorance of American teenagers on sexual matters, and other data suggest that a substantial segment of the public favors a sex education program in the schools, implementation has been limited. A questionnaire designed to test the feelings of public school teachers, students and community members was undertaken in a stable, conservative town of 1000 in Ohio. Respondents were asked to indicate which of 17 sex education topics should be included in a curriculum, the appropriate grade level for each, and whether each should be required or elective. They also ranked potential types of instructors, indicated interest in adult sex education, and rated desirability of student-parent and coeducational classes. The 1st choice for teacher type was a "sex education specialist," followed by a physician. Slightly over 1/2 of teachers favored parent-child sex education classes, but fewer than 25% of students did. Almost 2/3 of students favored coed classrooms for sex education, while 47.5% of teachers, about 1/3 of parents of school-age children, and fewer than 1/4 of persons without school-age children saw this as desirable. Teachers were most in favor of adult sex education (83.8%), and nearly 2/3 of all adults responded positively. A majority of all respondents favored including all 17 topics listed in a curriculum, but modal percentages of parents and persons without school-age children favored dropping masturbation and abortion from the sex education classroom, and homosexuality and premarital sexual relationships also met substantial opposition. Most groups agreed that with few exceptions sex education topics were most appropriate for grades 7-9. Although an expected strong resistence to sex education was not found, cautious administrators can find a number of reasons to avoid implementing sex education.     

Neonatal herpesvirus sepsis following internal monitoring

The use of internal monitoring, in which an electrode is attached to the fetal scalp, may be associated with serious complications. The authors present a case of fetal neonatal sepsis due to herpesvirus arising at the electrode site.     

Aspirin pretreatment reduces ethanol withdrawal severity in a mouse model of binge drinking.

Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin, which inhibit prostaglandin (PG) synthesis, have a pronounced effect on a broad range of ethanol (EtOH) actions. Given this, it is somewhat surprising that NSAID treatment has not been found to alter major signs of ethanol withdrawal. To date, the only effect found has been indirect, that is, NSAID treatment reduces the efficacy of PG precursor administration in the treatment of ethanol withdrawal via the inhibition of PG formation. However, in those studies reporting negative results NSAID administration was delayed until EtOH withdrawal. Studies demonstrating NSAID-related attenuation of other actions of EtOH have typically employed a pretreatment paradigm in which NSAIDs are administered prior to, not after, ethanol exposure. Thus, it may be that the point in the ethanol exposure/withdrawal episode at which NSAIDs are administered could be crucial in determining their effects of the ethanol withdrawal syndrome. To address this issue, we employed a multiple-exposure "binge drinking" model. On each of 6 treatment days, male BALB/c mice were injected subcutaneously with either acetylsalicylic acid (ASA, 150 mg/kg) or the buffer vehicle, followed 1 h later by either ethanol (4.0 g/kg) or saline (0.9%) by gavage. Ethanol withdrawal severity, as measured by handling-induced convulsions, was determined 2, 4, 6, 8, 10, 12, and 24 h after EtOH gavage. ASA pretreatment was found to significantly reduce handling-induced convulsions in ethanol-intubated animals. In fact, the attenuation was of such a magnitude that the ASA-pretreated ethanol group did not significantly differ in withdrawal severity from non-ethanol-exposed controls. This effect was not likely due to ASA-related alterations in ethanol pharmacokinetics. These findings have relevance for the understanding of the basic mechanisms underlying ethanol dependence, as well as the potential role of PGs in this phenomenon.     

Behavioral evidence for brain-based ability factors in visuospatial information processing

The present study examined possible parallels between the structure of human visuospatial abilities and the organization of the neural systems. Forty-eight participants were tested on seven speeded visuospatial tasks. Three of these tasks were constructed so as to rely primarily on known ventral stream functions and four were constructed so as to rely primarily on known dorsal stream functions. Both sets of tasks spanned approximately the same range of difficulty as indexed by both the speed and accuracy of decision making. Factor analysis of response times on the seven tasks revealed only two significant factors. The putative ventral stream tasks all loaded heavily on one factor (mean loading=0.843) but only weakly on the other factor (mean loading=0.222); the putative dorsal stream tasks showed the opposite pattern in that they all loaded heavily on the second factor (mean loading=0.828) but only weakly on the first factor (mean loading=0.229). These findings are consistent with the hypothesis that human visuospatial abilities can be classified using categories based on the specializations of underlying neural structures and systems.     

A chemically intelligent antimicrobial coating for urologic devices

Contact biocides are a relatively new form of infection-resistant materials. Surfacine is a silver based antimicrobial coating that can be immobilized on the surface of most alloplastic materials used to fabricate devices. It exhibits broad-spectrum antimicrobial activity exclusively at the surface without elution and does not induce antimicrobial activity in contacting fluids such as urine regardless of volume. Because it is permanently immobilized on the material surface, the coating is nontoxic to cells and is not anticipated to exhibit immunogenicity, teratogenicity, or carcinogenicity.