Human leukocyte antigen sensitization after structural cortical allograft implantations.

UNLABELLED: The incidence and significance of a donor-specific human leukocyte antigen antibody response to massive fresh-frozen human bone allograft implantation is not established. This study was a prospective, multicenter study of a cohort of consecutive patients who self-randomized themselves into two groups based on their alloantibody response to allograft bone transplant. The study hypothesis was that donor-directed antibodies are an independent risk factor influencing incorporation of massive frozen bone allografts. Pretransplant and posttransplant human leukocyte antigen alloantibody analysis was performed and correlated to determine pre-existing and graft-induced antibodies. The surgical outcomes of the two groups of patients were compared to determine the relationship between alloantibody response and bone graft incorporation. Preliminary results revealed that donor-specific human leukocyte antigen sensitization occurred in 17 of 32 (53%) of previously nonsensitized patients. A survival analysis of time to healing based on human leukocyte antigen status showed no evidence of an association between human leukocyte antigen status and time to healing. Longer followup in additional patients will be required to determine if this sensitization is correlated with an alteration in the time to union or with the quality or type of bone graft incorporation. LEVEL OF EVIDENCE: Therapeutic study, Level II. See the Guidelines for Authors for a complete description of levels of evidence.

Effects of social reorganization on cellular immunity in male cynomolgus monkeys.

Exposure to acute stressors has been shown to impair cellular immunity in human beings and other animal species. Comparatively little is known, however, about the effects of long-term stressors on immune function and how individual behavioral characteristics may mediate differences in immune function and clinical disease susceptibility. To determine the effects of social stress on cellular immunity and reactivation of a latent herpesvirus, 20 Herpes B virus-positive male cynomolgus monkeys were exposed to four periodic reorganizations of social group memberships over 5 months. Observations were made to categorize individuals as high or low in expression of aggressive, fearful, and affiliative behaviors. Complete blood counts, lymphocyte proliferation tests, and natural killer cell cytotoxicity assays were performed immediately before and 4 days after reorganizations. Herpesvirus-specific immunoglobulin G antibody levels were measured, and oral and conjunctival swabs were cultured for virus. Reorganization was associated with increased lymphocyte counts (P = 0.0009) and decreased lymphocyte proliferation in response to phytohemagglutinin (P < 0.005), particularly among monkeys showing high levels of fear (P = 0.0137). High-aggressive monkeys showed lower baseline natural killer cell activity (P = 0.0013) and higher lymphocyte counts (P = 0.013) than low-aggressive monkeys. Herpesvirus antibody titers decreased over time (P < 0.004) and no positive virus cultures were obtained. Measures of cellular immunity and behavior were unrelated to virus-specific antibody titers. These results suggest that repeated exposure to a social stressor alters several measures of cellular immunity, and that some of these changes may be predicted by individual differences in agonistic behavior. In contrast to human studies, the results suggest that some psychological stressors may not cause reactivation of a common herpesvirus in this species. © 1996 Wiley-Liss, Inc.

The relationship of agonistic and affiliative behavior patterns to cellular immune function among cynomolgus monkeys (Macaca fascicularis) living in unstable social groups.

Considerable recent interest has focused on the possibility that behavioral factors may influence immune competence, and hence, potentially, patterns of disease. We report here the relationship between the aggressive and affiliative behavior and the cellular immune responses of 30 adult male cynomolgus monkeys (Macaca fascicularis) living in small (n = 5) social groups whose members were periodically redistributed over 26 months. Animals also were subjected to behavioral observation, allowing them to be categorized as either high or low in aggressiveness and affiliation. At the end of the 26 months, lymphocyte proliferation tests were performed on blood samples from all monkeys, using both concanavalin A (ConA) and phytohemagglutinin (PHA) in concentrations of 1, 5, and 10 ug/ml. Two-by-two (Aggressiveness [high, low] X Affiliation [high, low]) analyses of variance performed on these data showed lymphocyte proliferation in response to both ConA and PHA to be greatest (at 1 ug/ml) among highly affiliative animals, albeit only if they were also low in aggressiveness (ConA: Affiliation x Aggression, P < 0.02; PHA: Affiliation x Aggression, P < 0.03). An additional finding was that natural killer cell activity (at an effector to target ratio of 100:1) was highest among highly affiliative animals, regardless of their aggressiveness (P < 0.05). These results indicate that immune competence may be enhanced among monkeys which, in response to a disrupted social environment, spend large amounts of time in affiliation with other animals. Social status, a phenomenon known to influence many aspects of nonhuman primate physiology, was unassociated with nonspecific lymphocyte blastogenesis or natural killer cell activity in this experiment.

Reactivity patterns of class I HLA monoclonal antibodies that distinguish three species of macaques.

The reactivity of a panel of 40 monoclonal antibodies (mAb) specific for HLA class I antigens was assessed in 117 unrelated Macaca mulatta (Mm), with a standard microcytotoxicity assay, in order to compare phenotypic frequencies with those previously reported for M. fascicularis (Mfl) and M. nemestrina (Mn). Based on the reactivity with HLA typed human cell panels, the epitopes recognized by these mAb in macaques were classified as nonpolymorphic, polymorphic "public," and polymorphic "private." Nei's genetic identity (I) and distance (D) formulae were applied to estimate I and D between each of the macaque species and between each macaque species and humans. The HLA nonpolymorphic epitopes emerged as spcies-specific determinants, as all three macaque species showed clear differences from each other and from humans in the frequency of occurrence in population samples. From our previous serologic study and from published sequence data, it is evident that the major histocompatibility complex (MHC) is highly conserved in primate evolution. Ninety percent of the mAb reacted at a similar frequency in either two or three macaque species. With few exceptions, the mAb reacted at a greater frequency in humans than in macaques. Concerning private HLA class I epitopes, we have previously speculated that the human MHC class I polymorphisms probably predate the diversification of macaque-human lineages, and hence would be highly conserved. However, the inconsistent pattern of occurrence of human monomorphic epitopes among the macaque species suggests that a complex explanation is required. One possibility is that HLA monomorphic epitopes are invariant in humans because of their yet unknown functional role; however, this explanation loses some force because of the inconsistent pattern of occurrence among three closely related species of Macaca. However, we favor a second possibility, i.e., that the monomorphic epitopes in humans might be the result of the accumulated neutral mutations and are not subjected to functional constraints. This explanation seems to fit the inconsistent pattern of occurrence of these epitopes among macaques.