Miodrag L. Lukic

A gene locus affecting tolerance to BGG in mice

Abstract A genetic analysis was made of the ease of tolerance induction to bovine γ-globulin (BGG) in DBA/2, BALB/c, F1 and backcross generation mice. Like parental DBA/2 mice, the F1 generation of BALB/c × DBA/2 becomes tolerant when treated with 2 mg BGG. A backcross of this F1 to DBA/2 parents produced mice that all became tolerant to this dose of BGG. A backcross of F1 mice to BALB/c parents produced 50% offspring tolerized by the same dose of BGG and 50% resistant to tolerance induction. The data suggest a single autosomal locus affecting tolerance induction. Data presented elsewhere suggest that the locus affects macrophage function. We propose that this locus be called tolerance (symbol Tol-l) and the two alleles be (Tol-la (DBA/2 type) and Tol-lb (BALB/c type) with Tol-la being dominant.

Strain-dependent Induction and Modulation of Autoimmunity by Mercuric Chloride in Two Strains of Rats

Publisher Summary This chapter presents a study to examine the strain differences in susceptibility to mercuric chloride-induced autoimmune syndrome in Albino Oxford (AO) and Dark August (DA) rats and the possible mechanisms responsible for the development of and/or resistance to mercury disease. For this study, mercuric chloride was administered to inbred AO and DA male rats, of 3–4 month old. Multiple subtoxic doses of mercuric chloride have a potent effect on the immune system of rats, and the outcome of this treatment is strain dependent. In the AO strain, which is resistant to Th1 type organ-specific autoimmune diseases, administration of mercuric chloride results in the production of various autoantibodies, followed by systemic autoimmune disorders and damages to renal tissue. In contrast, the DA strain, which is susceptible to Th1-mediated autoimmune diseases, did not develop autoantibodies and related manifestations in response to mercuric chloride. Although this treatment in DA rats probably promoted Th2 cytokine synthesis, indirectly proved by eosinophilia and inhibition of autoimmune diabetes, as in Th1-mediated disease, the net effect could be down-modulation of Th2 response due to the overproduction of Th1 cytokines.

Down-regulation of Th1 Mediated Autoimmune Pathology

Publisher Summary Cumulative evidence, gathered in recent years, demonstrate that the relative contributions of T-helper type 1 (Th1) and T-helper type 2 (Th2) CD4+ cells as landmarks of different effector pathways determine the destructive intensity of autoimmunity. Organ-specific autoimmune diseases develop as a consequence of expansion of self-reactive Th1 cells specific for relevant organ-specific autoantigen(s). The evidence obtained by analyzing the molecular and cellular basis of the differences in susceptibility to experimental allergic encephalomyelitis (EAE) and experimental autoimmune diabetes shows that the destructive autoimmune process may be modified at the level of the target tissue. The balance of cytokines and other mediators such as nitric oxide released locally by T cells, macrophages, and resident tissue cells determines the outcome of autoimmunity. The local balance of cytokines and other mediators determines the interplay between autoimmune and inflammatory mechanisms and severity of the disease. The realization that alterations in Th1/Th2 balance can be achieved by various means and that the production of proinflammatory cytokines and nitric oxide may be effectively blocked has opened the way for new therapeutic strategies.

THE CELLULAR BASIS FOR ESTABLISHING TOLERANCE OR IMMUNITY TO BOVINE γ-GLOBULIN IN MICE

Publisher Summary This chapter presents the cellular basis for establishing tolerance or immunity to bovine γ-globulin (BGG) in mice. In an experiment discussed in the chapter, the capacity of the reticuloendothelial systems of BALB/c and DBA/2 mice is compared to remove immunogenic material by studying biologic filtration in vivo . Large amounts of l25 I-trace labeled BGG were given to groups of mice of either strain. Two days later they were bled out and the amount of residual BGG in the serum was estimated by scintillation counting. Various doses of this biologically-filtered BGG were given to normal BALB/c mice and their subsequent development of tolerance or immunity was assessed in the usual way. The cell responsible for resistance to tolerance induction in BALB/c mice is especially capable of filtering out an immunogenic fraction of ultracentrifuged BGG; this ability is undiminished by lethal irradiation, is abrogated by a macrophage-toxic substance, and resides in an adherent cell population.

Cell-mediated immunity against allogeneic tumor after in vitro depletion of histocompatibility reactive cells

The “hot-pulse suicide” technique was first applied to lymphoid cells by Dutton and Mishell (1). The objective of this technique is to kill replicating cells in vitro by having them incorporate radioactive components such as thymidine, thereby eliminating the population proliferating in response to a specific antigen. Unidirectional mixed leukocyte cultures (MLC) “pulsed” with tri-tiated thymidine (3H-thy) of high specific radioactivity, for 3-36 hr 1 day after the initiation of the cultures were markedly inhibited in reactivity towards the stimulating cell but retained the capacity to respond to a second unrelated allogenic stimulus (2, 3). Similarly, MLC responses to a particular set of H-LA antigens can be suppressed by treatment with the thymidine analog 5-bro-modeoxyuridine (BUDR) followed by exposure to light in the visible or near visible region (4). This treatment does not significantly alter the capacity of the remaining lymphocytes to respond to cells of other H-LA specificity (4). Using the popliteal lymph node graft versus host (GVH) assay Rich et al. (5) demonstrated that Lewis rat spleen cells stimulated in mixed lymphocyte culture with F1 hybrid spleen cells in the presence of BUDR and then treated with light did not induce local GVH response in F1 recipients. Merino et al. (6) reported that Lewis rat spleen cells cultured with irradiated BN rat spleen cells and subjected to BUDR-light treatment are unable to elicit local GVH reaction under the kidney capsule of LBNF1 rats but they could still elicit GVH reaction in (L/BuF)F1 kidney. These findings suggested that GVH reactions which complicate bone marrow and lymphoid tissue transplantation could be controlled by selectively destroying the clones responding to histocompatibility antigens. Since the remaining cells retained their capacity to respond to other cellular antigens, it was possible to consider the application of the “hot pulse suicide” technique to sorting out cellular immune reactions to histocompatibility antigens from those directed against tumor specific antigens.