T-cell compartment involvement in two high antibody responder lines of mice (HI and HII Biozzi mice) respectively susceptible and resistant to collagen-induced arthritis.

The T-cell compartment was investigated in two high antibody responder lines of mice respectively susceptible (HI) and resistant (HII) to chicken collagen (CII)-induced arthritis (CIA). Previous data had shown that both lines were high anti-CII Ab producers, without any TCR V-beta gene defect or membrane expression impairment. The present studies demonstrate that anti-CII proliferation is much lower in HII than in HI.

Genetics of nonspecific immunity: I. Bidirectional selective breeding of lines of mice endowed with maximal or minimal inflammatory responsiveness.

The genetic regulation of acute inflammatory reaction (AIR) was studied by the method of bidirectional selective breeding, used to produce a line of mice giving the maximal and a line of mice giving the minimal inflammatory reaction (AIR max and AIR min, respectively). The AIR was triggered by subcutaneous injection of a neutral substrate (suspension of polyacrylamide microbeads), and measured by the leukocyte and serum protein accumulation in the exudate. The two parameters are positively correlated and present a normal frequency distribution.

Variations in susceptibility to Leishmania amazonensis infection in lines of mice selected for high or low immunoresponsiveness.

The degree of resistance to a local Leishmania amazonensis challenge has been compared in lines of mice obtained by selective breeding for high or low immunoresponsiveness: High and Low antibody responder mice of Selections I and II (HI, HII and LI, LII lines) and high and low responder mice to T mitogen PHA (Hi/PHA and Lo/PHA). The aim of this preliminary study was to focus attention on genetic differences related with well defined immune characteristics. Clear-cut results were obtained, both HI and HII mice developed large and disseminating lesions, the rate of symptom aggravation being faster in HII, while LI and LII proved resistant to parasites, only small and transient lesions being observed for them during a 150 days follow up.

Differential expression of migration inhibitory and migration stimulatory factors in two lines of mice genetically selected for high or low responsiveness to phytohemagglutinin. 2. Effects of mitogenic or allogeneic stimulation.

Expression of migration inhibition factor (MIF) following in vitro stimulation with phytohemagglutinin (PHA) or allogeneic cells was explored in two lines of mice genetically selected for the high (Hi/PHA) or low (Lo/PHA) response of their lymphoid cells to PHA. Hi/PHA mice also have greater cell-mediated immune responses in mixed lymphocyte culture and graft-versus-host reactions, the poorer cell-mediated immune response of Lo/PHA being accompanied by a higher frequency of malignant tumours. Expression of MIF in PHA-pulsed spleen cell supernatants measured by a sensitive photoelectric method was found to be modulated by the concomitant presence of migration stimulation factor (MStF) derived from T cells.

Differential expression of migration inhibitory and migration stimulatory factors in two lines of mice genetically selected for high or low responsiveness to phytohemagglutinin. 1. Migration stimulatory factor(s) from T and B cells of immune spleen.

Expression of the lymphokine migration inhibition factor in two lines of mice genetically selected for the high (Hi/PHA) or low (Lo/PHA) response of their lymph node cells to phytohemagglutinin was found to be modulated by concomitant expression of migration stimulation factor(s) [MStF(s)]. The expression of both lymphokines was dependent on genetic character and the immunizing dose of antigen. In mice immunized 5 days earlier with 50 micrograms ovalbumin in Freund's complete adjuvant (Ova in FCA immune), migration inhibition factor, assessed with a sensitive photoelectric method, was well expressed by male spleen or lymph node 24-hour culture supernatants of Lo/PHA but Hi/PHA, especially female, expressed marked MStF(s) instead.

Genetics of acute inflammation: inflammatory reactions in inbred lines of mice and in their interline crosses.

Acute inflammation is induced by the subcutaneous injection of swollen polyacrylamide microbeads, its intensity measured by the cell and protein concentration of the local exudates. A large and continuous range of responses is obtained in different inbred strains of mice, which suggests a polygenic control of the inflammatory response. The variable levels of the global dominance observed in F1 hybrids issued from several parental combinations indicated that the pattern of alleles controlling high or low response was different in each parental strain.

Impact of genetically regulated T cell proliferation on acquired resistance to Listeria monocytogenes.

Two lines of mice genetically selected for high and low in vitro responses to PHA were used to evaluate the impact of T cell polyclonal expansion on acquired resistance to Listeria monocytogenes. The selective breeding induced two major consequences in low responder mice: (1) a reduction of the number of L3T4+ cells and (2) a restriction of T cell expansion upon PHA stimulation, predominantly affecting the Lyt-2+ subset, and associated with an abridgment of IL-2 production. In vivo PHA stimulation induced anti-Listeria protection in high responder mice, but was much less effective in low responder mice.

Genetic regulation of multispecific antibody responsiveness: improvement of "high" and "low" characters.

The five selections carried out in the mouse for high or low antibody responsiveness to various multideterminant immunogens were successful. In all cases the large interline difference was shown to result from the additive effects of several independently segregating loci (polygenic regulation). However, important peculiarities were demonstrated in these original selections concerning either the cellular mechanisms operating or the effect of the selected genes on antibody responses to antigens unrelated with those used for the selection (multi-specific effect).

Genetic regulation of the specific and non-specific component of immunity.

Bi-directional selective breeding for antibody (Ab) responsiveness to heterologous erythrocytes (Selection I) produced a high (H) and a low (L) responder line of mice which were also remarkably separated for Ab responses to many unrelated natural antigens (Ags) such as heterologous proteins, viruses, bacteria, parasites and haptens carried by these immunogens. The character "quantitative Ab responsiveness" is controlled by several independently segregating loci (polygenic regulation). The major genetic modification is produced at the level of macrophage activities.

Genetic difference in the proliferative response to T mitogens between Hi/PHA and Lo/PHA lymphocytes is independent of accessory cell function.

The role of the macrophage as accessory cell in the proliferative response of lymphocytes to phytohemagglutinin (PHA) was studied in two lines of mice genetically selected for high and low responsiveness to T mitogens. Adherent cell depletion of lymph node cells abrogated the low (Lo)/PHA response, but only partially inhibited the high (Hi)/PHA response. Addition of peritoneal cells provided either by Hi/PHA or by Lo/PHA mice equally restored Hi/PHA responsiveness but had only a slight reconstituting effect on the inhibited Lo/PHA response.

Potentialities of immunocompetent cells in high and low antibody-producing lines of mice obtained by selective breedings for responsiveness to flagellar or somatic antigens of Salmonellae.

The genetic modifications of immunocompetent cell functions were investigated in high (H) and low (L) antibody responder lines of mice obtained by selective breeding for responsiveness to flagellar and somatic antigens of Salmonellae (Selection III and Selection IV, respectively). Several lines of evidence converge to demonstrate that the differences in antibody responses between the H and L lines of the two selections are not due to the modification of antigen handling by macrophages. This contrasts with previous observations that macrophages play a major role in interline differences in Selections I and II.

[Antitumoral activity of various doses of corynebacterium parvum as a function of the age of mice].

The anti-tumor activity of Corynebacterium parvum against two different tumours, a mammary carcinoma grafted in C3H mice and a lymphosarcoma grafted in XVII mice, was lower in young and old mice, than in adult ones. In young mice (25 days) of both lines, low doses of C. parvum were more efficient than higher doses.

Effects of T mitogens on in vivo antibody production to a T-dependent antigen in lines of mice genetically selected for high or low in vitro responsiveness to PHA.

The influence of genes which regulate the in vitro T-cell proliferative response to T mitogen upon in vivo antibody production to a T-dependent antigen was studied in two lines of mice genetically selected for a high or a low in vitro lymphocyte response to phytohaemagglutinin (PHA). Kinetics of agglutinin production to increasing doses of sheep erythrocytes was similar in the two lines, except for the titres of mercaptoethanol-resistant antibodies, which were slightly lower in the low-responder line. Treatment with mitogen prior to immunization modified the antibody response in the two lines differently.

Delayed hypersensitivity and migration inhibition in two lines of mice genetically selected for high or low responsiveness to phytohemagglutinin.

Delayed-type hypersensitivity (DTH) and cell migration inhibition (MI) were studied in two lines of mice genetically selected for the high (Hi/PHA) or low (Lo/PHA) in vitro response of their lymphoid cells to phytochemagglutinin (PHA). A rapid photoelectric procedure for reading cell migrations enabled the study of MI over a wide range (10 log) of antigen concentrations in vitro. Hi/PHA mice required immunization with a 10 times higher dose of ovalbumin (OVA) in Freund's complete adjuvant (FCA) than Lo/PHA mice for a comparable response in DTH (footpad swelling) and MI of their induced peritoneal exudate cells (PEC).

In vitro viability of lymphoid cells from lines of mice genetically selected for high or low responsiveness to phytohemagglutinin.

The kinetics of viability of lymph node and spleen cells of mice genetically selected for "high" or "low" in vitro lymphocyte responsiveness to PHA were studied in PHA or PPD-stimulated short-term cultures. Lo/PHA cells were found to be less viable than Hi/PHA cells in unstimulated control cultures. PHA improved the viability of Lo/PHA cells while inducing proliferation of Hi/PHA cells with the appearance of more and larger lymphoblasts in the latter.

Inheritance of post-vaccinal resistance against Plasmodium berghei infection in mice.

The protective effect of specific vaccination against Plasmodium berghei (P. berghei) was compared in terms of survival percentage in DBA/2, C3H, outbred albino mice and in two lines of mice produced by selective breeding for either high or low antibody responsiveness to sheep erythrocyte (H and L lines respectively). The efficacy of induced protection varies according to genetic constitution.

[Plasmodium berghei: antibody response and protective immunity induced by vaccination].

The authors have studied the behaviour of Swiss mice and of 5 inbred strains of mice in order to investigate: the protective effect, in the homologous infection test, of six vaccine inoculations of irradiated parasites belonging to two strains of Plasmodium berghei: ISTISAN and K173; the capacity to produce humoral antibodies after vaccine treatments and during infection; the probable correlation between the high antibody titre and the protection against infection. The results of the present study show that the antibody response plays a precise role in the immunity induced by vaccination. There is a certain degree of correlation, which is more evident for K173 vaccine, between the level of antibody response during infection and the protective efficacy of vaccination.

[Effect of the age of the mouse on the action of Corynebacterium parvum in inhibiting the growth of 2 syngenetic tumors].

The antitumor properties of Corynebacterium parvum have been studied in Mice of different ages of two inbred strains: XVII Mice and C3H Mice grafted with syngeneic tumors. The antitumor protection was very weak in young Mice: no effect on mortality rate, only an increase in mean survival time was observed. The highest level of protection was obtained in 2-5 month old Mice (100% of survival) In aged Mice this antitumor protection decreases more rapidly in C3H Mice than in XVII Mice.

[Passive transfer of "Corynebacterium parvum" anti-tumour protection by stimulated peritoneal cells ].

A partial anti-tumour protection can be induced by transfer of peritoneal cells from mice pretreated with Corynebacterium parvum, in the two experimental tumours studied: a mammary carcinoma syngeneic to C3H mice and a lymphosarcoma syngeneic to XVII mice. This protection is abolished by heating the peritoneal cells at 70 degrees C for 30 min, by a 2,200-rad irradiation or by a non-lethal irradiation of the recipient mice. Transfer of normal peritoneal cells did not produce any anti-tumour protection in C3H mice but induced the same effect as stimulated cells in XVII mice.

Tolerance induction in mice selected for high or low antibody responsiveness.

Induction of tolerance to bovine serum albumin was studied in mice selected for high (H) or low (L) antibody responsiveness and in their F1 hybrids. No high or low zone tolerances were obtained in H mice whereas L mice were susceptible to tolerance induction by the two schedules. H mice were immunized by repeated injections of tolerogenic BSA for low zone tolerance induction but not after the administration of a single high dose of tolerogenic BSA.

[Genetic control of immune responsiveness to bovine serum albumin in the high and low antibody producer lines of mice (author's transl)].

Mice genetically selected for high or low antibody responsiveness to sheep erythrocytes (SRBC) were used for a genetic analysis of the antibody response to an optimal dose of heat-aggregated bovine seralbumin (BSA). About 4 independent loci intervene in the quantitative genetic regulation of the response to BSA, while in these two lines the response to the selection antigen (SRBC) was found to be regulated by about 10 loci; one of them was linked to the major histocompatibility complex of the mouse (H-2). Such an H-2 linkage was not demonstrated for the regulation of the response to BSA.

[Genetic regulation of T-lymphocyte responsiveness to PHA is independent of culture conditions (author's transl)].

A maximal interline separation has been obtained after 10 consecutive generations of selective breeding for the character "quantitative in vitro response of lymph node lymphocytes to the mitogenic effect of phytohaemagglutinin". At the selection limit the difference between high and low responder lines was about 20-fold. A similar interline separation has been demonstrated for the T-mitogen effect of concanavalin A.