concanavalin-a and Osteopetrosis

Lymphocytes from osteopetrotic (op) rats, compared to their normal (n) littermates, exhibit defective immune functions associated with their inability to resorb bone. Among these immune defects are the failure of their spleen cells to proliferate normally to mitogens and to generate IL-2. Addition of exogenous IL-2 failed to reverse the suppressed proliferation in the op spleen cells, indicating that additional defects were involved in the suppression. Phenotypic analysis of cellular constituents of op and n spleens revealed that the percentages of T cells, macrophages, and IL-2 receptor positive cells were not different. Furthermore, there was no difference in CD4 (W3/25) and CD8 (OX8) cells. However, the Ia+ (OX3) cells in the op spleen represented less than 50% of those found in the n spleen, but the op had higher levels of transferrin receptor (OX26). On the basis of the ability of interferon-gamma (IFN-gamma) to increase Ia expression, this cytokine was added to op spleen cells (10-50 U/ml) and found to increase the number of Ia+ cells to the level found in n spleen cells. Moreover, pretreatment of op spleen cells with IFN-gamma restored their ability to proliferate to mitogens and their responsiveness to IL-2. Not only did IFN-gamma reverse the defective response to IL-2, but it also augmented the defective IL-2 production by op spleen cells. Taken together, these findings demonstrate that IFN-gamma can reverse many of the impaired immune functions characteristic of op spleen cells in vitro. Furthermore, these data suggest that IFN-gamma may provide an important avenue of treatment in these animals that may contribute to restoration of normal bone resorption.

Topics: Animals; Bone Resorption; Concanavalin A; Flow Cytometry; Histocompatibility Antigens Class II; Interferon-gamma; Interleukin-1; Interleukin-2; Lipopolysaccharides; Lymphocyte Activation; Lymphocyte Subsets; Macrophage Activation; Macrophages; Osteopetrosis; Rats; Rats, Mutant Strains; Receptors, Interleukin-2; Spleen

Infection of animals with oncogenic viruses frequently leads to an immunosuppressed state. We have examined immunosuppression induced by an avian osteopetrosis virus, myeloblastosis-associated virus of subgroup B inducing osteopetrosis [MAV-2(O)], and our results suggest that this virus induces immunosuppression by a novel mechanism. Lymphoid cells from osteopetrotic chickens did not respond to a wide dose range of concanavalin A (Con A) over a wide cell density range. Failure to undergo blastogenesis was not due to a lack of Con A-binding sites, since 125I-labeled Con A bound to lymphocytes from infected and uninfected chickens. Infected lymphocytes failed to respond to sodium metaperiodate stimulation, indicating that failure of blastogenesis was not due to a blockage of Con A receptor sites. MAV-2(O) infection of chicks 8 days of age resulted in a transient immunosuppression which appeared 1 to 2 weeks after infection. Cell-mixing experiments showed that MAV-2(O)-induced immunosuppression was not attributable to suppressor cells. In contrast, adherent cells from normal lymphoid preparations restored mitogenicity to lymphocytes from MAV-2(O)-infected animals. Adherent cells were present in the spleen and peripheral blood lymphocytes of MAV-2(O)-infected chickens in numbers comparable to those of the uninfected animal, and both sets of cells contained Fc-dependent phagocytic activity and nonspecific esterase. Peritoneal exudate cells were elicited from osteopetrotic and normal chickens in similar numbers. We conclude that MAV-2(O) induces immunosuppression by interfering with an accessory function of macrophage-like adherent cells.

Topics: Anemia; Animals; Avian Leukosis; Avian Myeloblastosis Virus; Chickens; Concanavalin A; Immune Tolerance; Lymphocyte Activation; Macrophages; Osteopetrosis; Receptors, Concanavalin A; Satellite Viruses; T-Lymphocytes, Regulatory

The restoration of normal bone remodeling in osteopetrotic animals by transplantation of spleen or bone marrow cells from normal littermates has suggested that the connective tissue abnormalities associated with this disease may be attributed to defective functions of the cells of the immune system. Examination of several immunologic parameters has revealed that both thymocytes and macrophages from osteopetrotic (op) rats express some dysfunctions but retain other activities. Mitogen-induced proliferation of thymocytes from affected rats is significantly lower than that of thymocytes from normal littermates. However, mitogen-activated thymocytes from op rats produce levels of a chemotactic lymphokine that are similar to those produced by the thymocytes from normal animals. Peritoneal exudate macrophages from op rats are defective in that they migrate minimally in response to a chemotactic lymphokine or C5a. These macrophages do, however, produce lymphocyte-activating factor as efficiently as those from the unaffected littermates. The results presented here, which document immunologic defects in the lymphocytes and macrophages from the op rat, indicate that multiple immunoregulatory mechanisms involved in the degradation of connective tissue may contribute to the skeletal malformations that are present in this animal model.

Topics: Animals; Chemotaxis; Concanavalin A; Immunity, Cellular; Lymphocyte Activation; Lymphocytes; Lymphokines; Macrophage Activation; Macrophages; Osteopetrosis; Rats; Rats, Mutant Strains