Human Innate Immune Response Research Articles

Role of Class-II Major Histocompatibility Complex (MHC)-Antigen–Positive Donor Leukocytes in Transfusion-Induced Alloimmunization to Donor Class-I MHC Antigens

AbstractIt has been shown that peripheral-blood mononuclear leukocytes (MNL) are responsible for transfusion-induced alloimmunization to donor major histocompatability complex (MHC) antigens. However, it is not known which subset of MNL is responsible for this immune response. Because elimination of class-II MHC antigen-positive passenger leukocytes effectively prolongs the survival of allografts, it has been hypothesized that class-II positive MNL are responsible for immunizing transfusion recipients to donor MHC antigens. To test this hypothesis, two different approaches were used. First, we compared the alloantigenicity of BALB/c mice (H-2d) peripheral blood MNL before and after depletion of class-II positive cells. CBA mice (H-2k) were used as transfusion recipients. Antibody development to donor class-I H-2 antigens was determined by flow cytometry and enzyme-linked immunoassay. After four weekly transfusions of MNL depleted for class-II positive cells, only 25% of recipient mice developed antibodies to donor H-2d antigens. In contrast, all mice transfused with control MNL became immunized. Second, we studied the alloantigenicity of peripheral MNL from C57BL/6 mice (H-2b) with homozygous deficiency of class-II MHC molecules in H-2 disparate recipient mice. After transfusions with class-II MHC molecule-deficient MNL, 0% of BALB/c, 40% of C57BR, and 25% of CBA-recipient mice developed antibodies to donor H-2b antigen. All control recipient mice were immunized. The antibody activities of the controls were also higher than those in the treatment group who became immunized. Thus, our study shows that class-II MHC antigen-positive MNL play a significant role in transfusion-induced alloimmunization to donor class-I MHC antigens. The results also support the hypothesis that direct antigen presentation by donor class-II positive MNL to the immune system of transfusion recipients is critical for the initiation of humoral immune response to donor MHC antigens.

Identification of the innate human immune response to surface-exposed proteins of coagulase-negative staphylococci

The presumed host defense against coagulase-negative staphylococci (ConS), recognized pathogens in hosts with compromised immunity or indwelling medical devices, is opsonophagocytosis. Targets for opsonization remain unclear. Using radiolabeling techniques, we identified the surface-exposed proteins of ConS and determined the innate humoral immune responses to them among healthy adults. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of surface proteins extrinsically labeled with 125I demonstrated 20 to 30 proteins with molecular weights of 15,000 to greater than 130,000. Five to ten of these proteins were immunogenic and recognized by normal human sera, including predominant 18-, 41-, 48-, and 51-kDa proteins. We also evaluated the humoral response of cancer patients with ConS bacteremia. Patients' sera obtained before bacteremic episodes demonstrated a pattern of reactivity similar to that of normal human sera. When patients' sera obtained after bacteremic episodes were used to determine whether an expanded immune response followed infection, only one of seven showed reactivity with more proteins than seen with the innate response. Western blot (immunoblot) analysis and whole-cell enzyme-linked immunosorbent assays were also evaluated. This study identifies (i) the surface-exposed proteins available for host interaction, (ii) the innate human antibody response to these proteins, and (iii) the immune response of cancer patients with ConS bacteremia.

Magainins, a class of antimicrobial peptides from Xenopus skin: Isolation, characterization of two active forms, and partial cDNA sequence of a precursor

Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings.

Lymphocyte trapping in tolerant mice.

THE precise nature of the cellular defects involved in a state of immunological unresponsiveness remains to be elucidated1. As one of the earliest events in the initiation of humoral immune responses is the recruitment of peripheral lymphocytes6–11, we have investigated the kinetics of recruitment in tolerant animals.