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The experiments described in this paper extend the observations of previous work in vitro demonstrating a decrease in the frequency of antigenreactive units specific for horse RBC in spleen cells from mice primed with KLH. It was observed that the addition of lymphoid cells having T-cell function reconstituted the anti-HRBC response to normal values. Significant enhancement of the response beyond the normal values could be evoked using two dissimilar methods, (i) addition of allogeneic thymus cells, and (ii) restimulation in vitro with the priming antigen. The latter type enhancement was elicited by the addition of small doses of KLH to cultures of spleen cells from mice recently primed with KLH, including cultures otherwise demonstrating antigen-induced suppression. The stimulus required to enhance the response to HRBC in these cultures was specific for the priming antigen, KLH. These results are discussed in the light of current theories of 'antigenic competition' and specific heterologous enhancement. [ABSTRACT FROM AUTHOR]

The immunological responses of rabbits to HSA, HGG or BSA were tested at various times later in animals which had received the corresponding antigens before or shortly after birth. As judged by the criterion of failure to show immune elimination of antigen, a high proportion of the rabbits remained unresponsive at times when it was calculated that all the originally administered antigen would have been eliminated from the circulation. Furthermore, removal of antigen by passively administered antibody failed to restore the capacity to respond. It is concluded that, in respect of the antigens used, their persistence in the extracellular body fluids is not a prerequisite for maintenance of immunological unresponsiveness.
Further administration of the same antigen to rabbits which had escaped from a state of specific immunological unresponsiveness generally produced a very weak response, and in a few instances resulted in a return to the unresponsive state.
When the cross-reacting antigens HSA and BSA were administered adsorbed on alum to rabbits made unresponsive by neonatal contact with BSA and HSA respectively, and at the same time a further dose of the original antigen was given, antibodies were formed which were specific for the second antigen and did not cross-react with the first. In only 1/9 animals was responsiveness to the first antigen restored. The significance of these results is discussed. [ABSTRACT FROM AUTHOR]

The enhancement effect of some antigens on in vitro colony formation by normal mouse bone marrow cells is mediated through a normal serum αmacroglobulin (αM) which is present in newborn animals and shows no immunological specificity. The proportion of antigen and αM affects colony enhancement, and it has also been shown that specific antibody successfully competes with αM for the antigen. It seems likely that antigen-αM complex acts directly on the colony forming cell, rather than indirectly through release of colony stimulating factor. The possible relevance of this phenomenon to immune induction and, to the effect of antigens in promoting irradiation survival is discussed. [ABSTRACT FROM AUTHOR]

India ink or other finely divided agents (trypan blue, saccharated iron oxide, thorotrast, polystyrene latex) were injected intravenously into mice, and sheep erythrocyte stroma injected subsequently by the same route. The splenic uptake of stroma carrying a tag of 131I was consistently higher in mice treated with the 'blockading' agents than in untreated controls, the difference in some experiments being greater than ten-fold. In addition to promoting the splenic uptake of antigen, some of the finely divided agents also enhanced the formation of anti-sheep red cell haemolysin in mice immunized with a single intravenous injection of sheep erythrocyte stroma. India ink injected intravenously caused a significant rise in the splenic weight of mice. [ABSTRACT FROM AUTHOR]

Rabbit hyperimmune γ-globulin was produced against type 5 adenovirus. This was digested with pepsin to produce bivalent fragments of antibody. These fragments retained the capacity to precipitate with antigen, but were defective in their power to neutralize virus infectivity. Their neutralizing capacity deviated from that of native antibody in the following ways : The proportion of virus neutralized was smaller. The progressive neutralization of virus ceased within 10–15 minutes of mixing virus and fragments of antibody. The rate of neutralization of virus depended only on the concentration of fragments of antibody, and was independent of the relative proportions of virus and antibody fragments. Over the ranges tested the antibody fragments inactivated an approximately constant proportion of virus irrespective of the amount of virus used in the primary, mixture. There is a brief discussion of the significance of these results for an understanding of the mechanism by which complete antibody neutralizes virus infectivity. [ABSTRACT FROM AUTHOR]

Rabbits were immunized with bovine (BSA) or human (HSA) serum Albumin. Spleen cell suspensions were prepared and incubated with the homologous or cross-reacting albumins. The antigen-dependent stimulation of the rate of DNA synthesis was used as a measure of the antigenic activity of each of the albumin preparations. The response was proportional to the logarithm of the antigen concentration for both the homologous and the cross-reacting albumins and the slopes of each curve were approximately the same. The cross-reacting albumins were less stimulatory than the homologous antigen. The pattern of their relative activities in this system tbllowed the same pattern shown in their serological cross-reactions. [ABSTRACT FROM AUTHOR]

Rats, injected with crude bovine heart extracts, showed dissociation of their immunological response. Complement-fixing and capillary precipitating anti-bodies were produced, active against particulate antigens, while tanned-cell haemagglutinating and gel-diffusing antibodies were active against soluble antigens. Particulate antigens were centrifuged down from tissue extracts as 60,000 g but not at 12,000 g. The kinetics of production and specificity differed in the two groups of antibody. When rats were injected with bovine tissues from birth, to produce immuno-tolerance, they did not produce complement-fixing or capillary precipitating antibodies on later challenge with bovine heart but did produce haemagglutinating and gel-diffusing antibodies. Even before challenge, pretrated rats showed haemagglutinating antibodies, while the response by this test to the further immunization was partially suppressed. [ABSTRACT FROM AUTHOR]

The immune responses of the turkey and fowl to intra-rectal infections with tissue containing Histomonas meleagridis were studied. A protective immunity was produced in drug-treated turkey and in fowls recovering spontaneously. These birds develop precipitating antibodies in their sera to an antigen derived from H. meleagridis. Antigen was first detected in caecal contents 4 days after infection and serum precipitins 7 days later. It was not possible to transfer protective immunity by injections of serum from immune to susceptible birds. [ABSTRACT FROM AUTHOR]

Using a local passive transfer system in mice it has been possible to detect interaction between sensitized lymph node cells and antigen inducing contact sensitivity. Cells were injected into the ears of mice intracutaneously and antigen applied to the skin. A late inflammatory" response at the site was detected by measuring the 24-hour uptake of 51Cr-labelled indicator ‘inflammatory cells’ (peritoneal exudate or oxazolone-sensitized lymph node cells). Three days after local transfer the uptake in ears receiving sensitized cells and challenged with antigen was three-to ten-fold greater than in the ears of animals receiving cells or antigen alone. This phenomenon was dependent upon challenge with the appropriate antigen. Interaction was also detected when cells were transferred into one ear and antigen applied to the other. Experiments to explain this effect showed that transferred cells disappeared rapidly from the site of transfer. Antigen applied elsewhere enhanced their mobility and increased their arrival at the antigen site. [ABSTRACT FROM AUTHOR]

The induction and loss of tolerance to native and depolymerized fractions of levan, a thymus-independent antigen, have been studied in (DBA/1 × CBA-T6T6)F1 mice by a direct plaque-forming cell (PFC) assay. Tolerance following 1 mg native levan began to break by 80 days, whereas mice remained specifically unresponsive 150 days after 10 mg. Effects attributable to long persistence of antigen have been demonstrated. The following main features of levan tolerance were established by transfer of spleen cells to 900 R-irradiated recipients: (1) the induction period is very short—less than 24 hours. (2) No detectable immunity accompanies or precedes induction. (3) The fall in immunogenicity with reduction in molecular weight (mol. wt) of levan is not accompanied by loss of tolerogenicity. An effectively tolerogenic, non-immunogenic fraction (mol. wt< 10,000) was found. (4) There is no rapid loss of tolerance following cell transfer (reactivity is only regained after 50 days), arguing against the existence of tolerant cells in this model. As these results and those from corresponding investigations with SIII and HGG all show major dissimilarities, it is considered imprudent to base generalizations concerning the nature of B cell tolerance on studies with only one type of antigen. Whether or not two different kinds of specific unresponsiveness might be implicated with these cells is discussed. [ABSTRACT FROM AUTHOR]

The immunological response to native levan (a fructose homopolymer with molecular weight 2 × 107) has been studied in (DBA/1 × CBA-T6T6)F1 mice by passive hemagglutination and plaque-forming cell (PFC) assays. It resembles type-specific pneumococcal polysaccharide (SSS) in eliciting a prolonged humoral antibody response over a wide dose range (0.0001-100 µg) and in inducing longlasting 'high zone' tolerance with a single injection (1 mg or more). Other similarities include an exclusively IgM response, independence of synergy with thymusderived lymphocytes and absence of immunological memory. On the other hand, parallelism between serum hemagglutinin and PFC levels following all doses of antigen implies that higher immunizing doses of levan, unlike SSS, do not engage in peripheral neutralization of antibody. It was concluded from studying the fate of 14C-labelled levan that this was attributable to more rapid elimination from the circulation and subsequent slow metabolism of this polysaccharide. Levan also differs from SSS in inducing tolerance directly, without a detectable prior immune phase. [ABSTRACT FROM AUTHOR]

An analysis was made of the antibody response in the spleen and lymph nodes of mice to erythrocyte antigens injected under conditions which have been reported to cause antigenic competition. In the spleen, injection of a different erythrocyte antigen 2-4 days before the injection of a test antigen had little or no effect on the total number of cells or the number of plaque-forming cells (PFC) to the test antigen. Examination of the antibody response in opposite lymph nodes of a mouse made possible a comparison between two different conditions of antigen exposure within the same individual. In the lymph nodes, preceding the injection of the test antigen by an injection of a different erythrocyte antigen 2-4 days earlier led not to a decrease, but, on the contrary, to an increase in the number of plaque forming cells to the test antigen. A similar increase in the number of plaque-forming cells per lymph node was observed for each of two test antigens, when these had been mixed and injected into the forefeet 24 hours after the injection of a different erythrocyte antigen. [ABSTRACT FROM AUTHOR]

The effect of prior administration of two classes of 7S mouse anti-sheep red blood cell (SRBC) antibodies on the primary immune response to SRBC was studied. Mouse γG1 and γG2 immunoglobulins were isolated from serum by zone electrophoresis and density gradient isolectric focusing. The immunoglobulins were defined by qualitative and quantitative studies, and their effects on the primary response were determined by administering doses ranging from 0.5 to 0.001 mg of immunoglobulin 2 hours before injection of antigen. Gamma G1, antibody suppressed the response to SRBC at all concentrations. High doses of γG2 antibody partially suppressed 19S plaque-forming cells (PFC), but had no significant effect on serum haemagglutinin (HA) levels. Low doses of γG2 antibody specifically augmented both the 19S PFC and serum HA levels. It is concluded that the specific suppressing and augmenting influences of antibodies on the primary response are a function of class. In addition, it is proposed that &gammaG1, and γG2 antibodies can aet as specific regulatory elements during the primary response by exerting these two competing biological effects on antibody synthesis. [ABSTRACT FROM AUTHOR]

In the antibody response to rabbit IgG in BALB/c mice, antigenic competition has been demonstrated between Fc and Fab'. Similar competition was found when a mixture of Fc and Fab' was used as antigen. In both cases the presence of Fc suppressed the antibody response to Fab'. Competition was demonstrable only in the primary antibody response. The effect on competition of varying the mutes and the time course of administration of the antigens was investigated. [ABSTRACT FROM AUTHOR]

After injection of several antigens, synthesis of specific antibodies is, in all studied cases, accompanied by synthesis of immunoglobulins unable to react with the antigen. The ratio between non-reactive immunoglobutins and specific antibodies decreases during successive immunizations. The immune response to two different antigens (TMV and BSA) is very similar: antibody levels in the serum and numbers of antibody secreting cells in file spleen of immunized animals are nearly identical. When these two antigens are simultaneously injected in rabbits, each antigen seems to initiate independently proliferation of antibody secreting cells and of non-reactive immunoglobulin secreting cell populations. The meaning of these results is discussed. [ABSTRACT FROM AUTHOR]

Dvorak and Flax (1966) and others reported that adult guinea-pigs pretreated with soluble antigens showed depressed immune responses following immunization with the same antigens in Freund's complete adjuvant. These depressed immune responses included haemolytic and cytophilic antibody and delayed hypersensitivity as well as antibody measured by passive cutaneous anaphylaxis and haemagglutination. This communication describes further studies on the effect of pretreatment with alum precipitated bovine γ-globulin rather than soluble antigen. Guinea-pigs given 1 mg of alum precipitated bovine γ-globulin prior to immunization with 50 µg bovine γ-globulin (BGG) in Freund's complete adjuvant show depressed haemolytic and cytophilic antibody and delayed hypersensitivity. This depression is immunologically specific as pretreatment with alum precipitated egg albumin does not depress immune responses to bovine γ-globulin. In contrast, antibody measured by passive cutaneous anaphylaxis and haemagglutination is either unaffected or raised. Similarly, pretreatment with sheep red cells reduces the cytophilic antibody response to sheep red cells in Freund's complete adjuvant. This depression is long lasting and 1 mg alum precipitated BGG depressed the haemolytic antibody response to BGG in adjuvant given 6 months later and the delayed hypersensitivity response to BGG in adjuvant given 9 months later. Alum precipitated BGG given up to 6 days after immunization with BGG in adjuvant caused some depression of haemolytic antibody. However, this depression was transient and much less than the long lasting depression caused by pretreatment with alum precipitated BGG 7 days before immunization with BGG in adjuvant. The effect of irradiation followed by alum precipitated BGG on the immune responses to BGG in Freund's complete adjuvant was also studied. 300 r depressed haemolytic and haemagglutinating antibody but had no effect on cytophilic antibody or delayed hypersensitivity. There was no synergy between irradiation and pretreatment with BGG; the depression of immune responses caused by irradiation followed by alum precipitated BGG was no greater than the depression caused by the more effective agent when given alone. [ABSTRACT FROM AUTHOR]

The incorporation of some antigens such as bacterial endotoxin, heterologous erythrocytes and bacterial flagellin preparations can enhance the formation of colonies in cultures of normal mouse bone marrow or foetal liver cells in vitro. Other antigens such as foreign serum proteins and haemocyanin are inactive. This effect depends on the reaction of antigen with a component of normal mouse serum. [ABSTRACT FROM AUTHOR]

It has been shown that intraperitoneal injection of Freund's complete adjuvant can stimulate the multiplication and effect the distribution within the animal of cells which form granulocytic and monocytic colonies in vitro. This response is associated with a leukocytosis and a fall in haematocrit. A variety of antigens were tested all of which resulted in an increase in the number of colony forming cells in the spleen to a greater or lesser degree. Two mechanisms are thought to be involved in this response: (1) with some antigens a direct stimulation of colony forming cells by an antigen-α-macroglobulin complex; and (2) an indirect stimulation of colony forming cells by release of colony stimulating factor from cells other than the colony forming cells. [ABSTRACT FROM AUTHOR]