Network regulation of the immune response: alternative control points for suppressor modulation of effector lymphocytes

The network theory of the immune response proposed by Jerne has stimulated considerable interest, and a large body of evidence supporting this theory has been produced. However, the structure and function of the immune network have not been precisely defined. In this paper we develop several criteria to compare alternative systems on the basis of function and then examine mathematically the functional significance of two interactions involving suppressor regulation of effector lymphocytes in normal immune responses. The interactions examined in detail are suppressor regulation of the production of effector lymphocytes and suppressor regulation of the clearance of effector lymphocytes. The approach is one that has been used previously to predict and characterize function and design in biochemical and genetic control systems. The results of our analysis suggest that an immune system with suppressor regulation of the production of effector lymphocytes is equal or superior to a system without this form of regulation on the basis of all of the criteria examined in this study. Also, a system with regulation of the clearance of effector lymphocytes can be equal or superior to a system without this form of regulation on the basis of six criteria, but it is inferior to such a system on the basis of one criterion. Furthermore, a system with regulation of both production and clearance of effector lymphocytes is equal or superior to a system without regulation of production on the basis of all of the criteria and can be equal or superior to a system without regulation of clearance on the basis of six criteria, but it is inferior to such a system on the basis of one criterion. Similar conclusions hold for the comparison of systems in which regulation is exerted upon the production or clearance of effector molecules, such as antibodies or free radicals.     

Idiotype and antigen-specific T cell responses in mice on immunization with antigen, antibody, and anti-idiotypic antibody.

Idiotypic determinants of immunoglobulin molecules can evoke both CD4(+) and CD8(+) T responses and exist not only as the integral components of a bona fide antigen binding receptor but also as distinct molecular entities in the processed forms on the cell surface of B lymphocytes. The present work provides experimental evidence for the concept that regulation of memory B cell populations can be achieved through the presentation of idiotypic and anti-idiotypic determinants to helper and cytotoxic cell. The potential of B cells to present antigens to helper and cytotoxic T cells through class II and class I MHC suggests a mechanism by which both B and T cell homeostasis can be maintained. We provide evidence for the generation of idiotype- and antigen-specific Th and Tc cells upon immunization of syngenic mice with antigen or idiotypic antibody (Ab1) or anti-idiotypic antibody (Ab2). The selective activation and proliferation of the antigen-specific Th and Tc cells mediated by idiotypic stimulation observed in these experiments suggests a B-cell-driven mechanism for the maintenance of antigen-specific T cell memory in the absence of antigenic stimulation, under certain conditions.     

The regulation of resistance to Schistosoma mansoni by auto-anti-idiotypic immunity. III. An analysis of effects on epitopic recognition, idiotypic expression, and anti-idiotypic reactivity at the clonal level.

Auto-anti-idiotypic mechanisms can regulate the protective immune response against Schistosoma mansoni. Anti-idiotypic responses were stimulated by immunization of mice either with nonspecifically induced lymphoblasts, produced with Con A, or with Ag-induced lymphoblasts bearing specific idiotypic receptors. The effect of the induced anti-idiotypic response upon clonotypic cellular reactivity was assessed in vitro through the suppression of antigen-mediated blast transformation by cloned T cells and in vivo by suppression of resistance to S. mansoni and delayed-type hypersensitivity responses against specific Ag. Differential regulation of humoral immune responses was studied at the levels of specific epitopic recognition, the expression of specific Id, and the production of anti-idiotypic responses directed against mAb bearing specific Id. Anti-idiotypic sensitization resulted in variable (10 to 90%) suppression of the immune response to discrete antigenic epitopes, the expression of specific idiotypic phenotypes, and anti-idiotypic, antiparatopic responses against T cell clonotypes and antibody idiotypic phenotypes. In vitro admixture and in vivo challenge studies resulted in consonant differential suppression. Thus idiotypic regulation can mold the fine specificities of the protective immune response to S. mansoni at the clonal level and may provide an approach to optimize the expression and assessment of resistance.     

Memory but no suppression in low-dimensional symmetric idiotypic networks

We present a new symmetric model of the idiotypic immune network. The model specifies clones of B-lymphocytes and incorporates: (1) influx and decay of cells; (2) symmetric stimulatory and inhibitory idiotypic interactions; (3) an explicit affinity parameter (matrix); (4) external (i.e. non-idiotypic) antigens. Suppression is the dominant interaction, i.e. strong idiotypic interactions are always suppressive. This precludes reciprocal stimulation of large clones and thus infinite proliferation. Idiotypic interactions first evoke proliferation, this enlarges the clones, and may in turn evoke suppression. We investigate the effect of idiotypic interactions on normal proliferative immune responses to antigens (e.g. viruses). A 2-D, i.e. two clone, network has a maximum of three stable equilibria: the virgin state and two asymmetric immune states. The immune states only exist if the affinity of the idiotypic interaction is high enough. Stimulation with antigen leads to a switch from the virgin state to the corresponding immune state. The network therefore remembers antigens, i.e. it accounts for immunity/memory by switching beteen multiple stable states. 3-D systems have, depending on the affinities, 9 qualitatively different states. Most of these also account for memory by state switching. Our idiotypic network however fails to account for the control of proliferation, e.g. suppression of excessive proliferation. In symmetric networks, the proliferating clones suppress their anti-idiotypic suppressors long before the latter can suppress the former. The absence of proliferation control violates the general assumption that idiotypic interactions play an important role in immune regulation. We therefore test the robustness of these results by abandoning our assumption that proliferation occurs before suppression. We thus define an “escape from suppression” model, i.e. in the “virgin” state idiotypic interactions are now suppressive. This system erratically accounts for memory and never for suppression. We conclude that our “absence of suppression from idiotypic interactions” does not hinge upon our “proliferation before suppression” assumption.     

Unreasonable implications of reasonable idiotypic network assumptions

We first analyse a simple symmetric model of the idiotypic network. In the model idiotypic interactions regulate B cell proliferation. Three non-idiotypic processes are incorporated: (1) influx of newborn cells; (2) turnover of cells: (3) antigen. Antigen also regulates proliferation. A model of 2 B cell populations has 3 stable equilibria: one virgin, two immune. The twodimensional system thus remembers antigens, i.e. accounts for immunity. By contrast, if an idiotypic clone proliferates (in response to antigen), its anti-idiotypic partner is unable to control this. Symmetric idiotypic networks thus fail to account for proliferation regulation. In high-D networks we run into two problems. Firstly, if the network accounts for memory, idiotypic activation always propagates very deeply into the network. This is very unrealistic, but is an implication of the “realistic” assumption that it should be easier to activate all cells of a small virgin clone than to maintain the activation of all cells of a large (immune) clone. Secondly, graph theory teaches us that if the (random) network connectance exceeds a threshold level of one interaction per clone, most clones are interconnected. We show that this theory is also applicable to immune networks based on complementary matching idiotypes. The combination of the first “percolation” result with the “interconnectancr” result means that the first stimulation of the network with antigen should eventually affect most of the clones. We think this is unreasonable. Another threshold property of the network connectivity is the existence of a virgin state. A gradual increase in network connectance eliminates the virgin state and thus causes an abrupt change in network behaviour. In contrast to weakly connected systems, highly connected networks display autonomous activity and are unresponsive to external antigens. Similar differences between neonatal and adult networks have been described by experimentalists. The robustness of these results is tested with a network in which idiotypic inactivation of a clone occurs more generally than activation. Such “long-range inhibition” is known to promote pattern formation. However, in our model it fails to reduce the percolation, and additionally, generates semi-chaotic behaviour. In our network, the inhibition of a clone that is inhibiting can alter this clone into a clone that is activating. Hence “long-range inhibition” implies “long-range activation”, and idiotypic activation fails to remain localized. We next complicate this model by incorporating antibody production. Although this “antibody” model statically accounts for the same set of equilibrium points, it dynamically fails to account for state switching (i.e. memory). The switching behaviour is disturbed by the autonomous slow decay of the (long-lived) antibodies. After antigenic triggering the system now performs complex cyclic behaviour. Finally, it is suggested that (idiotypic) formation of antibody complexes can play only a secondary role in the network. In conclusion, our results cast doubt on the functional role of a profound idiotypic network. The network fails to account for proliferation regulation, and if it accounts for memory phenomena, it “explodes” upon the first encounter with antigen due to extensive percolation.     

Antigen-specific inhibition of immune interferon production by suppressor cells of autoimmune encephalomyelitis

Previous work from this laboratory has revealed that spleen and/or lymph node cells from Lewis rats, that have recovered from an acute episode of experimental autoimmune encephalomyelitis (EAE), suppress the development of EAE when injected into syngeneic recipients subsequently challenged with myelin basic protein (MBP) in CFA. In an effort to understand the mechanism of this suppression, we measured the production of immune IFN-gamma, which may be required for the induction of an immune response, by EAE effector T cells (which transfer disease) and EAE suppressor cells when cultured in vitro with MBP. We now report that EAE effector T cells produce IFN-gamma when cultured in vitro with MBP. In contrast, spleen cells from recovered rats (which manifest suppressor activity in vivo) do not produce IFN-gamma. Moreover, in cell mixing experiments, these suppressor spleen cells inhibited the production of IFN-gamma by EAE effector cells. This inhibition was not eliminated by the removal of macrophages nor by the inhibition of PG synthesis by indomethacin. Furthermore, the inhibition was shown to be Ag-specific and mediated by nylon-adherent, radiation-sensitive splenic T cells. The findings suggest that suppressor cells regulate EAE by inhibiting IFN-gamma production by effector cells. This inhibition may result in the down-regulation of IFN-gamma-induced expression of class II major histocompatibility Ag on cells of the central nervous system, thus reducing the presentation of tissue-specific Ag (i.e., MBP) to autoreactive lymphocytes.     

Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression

Activation-induced cell death is a general mechanism of immune homeostasis through negative regulation of clonal expansion of activated immune cells. This mechanism is involved in the maintenance of self- and transplant tolerance through polarization of the immune responses. The Fas/Fas-ligand interaction is a major common executioner of apoptosis in lymphocytes, with a dual role in regulatory T cell (Treg) function: Treg cell homeostasis and Treg cell-mediated suppression. Sensitivity to apoptosis and the patterns of Treg-cell death are of outmost importance in immune homeostasis that affects the equilibrium between cytolytic and suppressor forces in activation and termination of immune activity. Naive innate (naturally occurring) Treg cells present variable sensitivities to apoptosis, related to their turnover rates in tissue under steady state conditions. Following activation, Treg cells are less sensitive to apoptosis than cytotoxic effector subsets. Their susceptibility to apoptosis is influenced by cytokines within the inflammatory environment (primarily interleukin-2), the mode of antigenic stimulation and the proliferation rates. Here, we attempt to resolve some controversies surrounding the sensitivity of Treg cells to apoptosis under various experimental conditions, to delineate the function of cell death in regulation of immunity.     

Regulation of contact sensitivity reaction: contrasuppressor T cells and contrasuppressor factor downregulate efferent T suppressor cells.

Contact sensitivity (CS) reaction mediated by CD 4+8- Th 1 cells is under the control of several antigen-specific regulatory lymphocytes. Reaction is downregulated at the induction stage by T afferent suppressor T cells (Ts-aff) that prevent immunization and at the effector stage by efferent T suppressor cells (Ts-eff) that made immune Th 1 cells inoperative. Both suppressor cells are CD 4-8+ Th 1 effector cells and are protected against the suppressive action of Ts-eff cells by CD 4+8- contrasuppressor T cells (Tcs). As has been already shown there are also regulatory interactions between regulatory cells themselves and Ts-aff cells in addition to their effect on precursors of Th 1 cells, also preventing the induction of Ts-eff cells. The present experiments extend these findings and demonstrate that Ts-eff cells are also under negative control of Tcs lymphocytes. Likewise, antigen-specific factor produced by contrasuppressor T-T cell hybridoma, used in lieu of Tcs cells, impedes the activation of Ts-eff cells. In both cases regulation is aimed at the precursors of Ts-eff cells. Our experiments demonstrate that the outcome of immunization is dependent not only on the balance between immune cells and regulatory cells, but also on interactions between regulatory cells themselves.     

Brief antigenic stimulation generates effector CD8 T cells with low cytotoxic activity and high IL-2 production

It is currently believed that a brief antigenic stimulation is sufficient to induce CD8 T cells to complete their differentiation program, become effector T cells, and subsequently generate memory. Because this concept was derived from studies in which only a single effector function was analyzed (either IFN-gamma production or target cell lysis), we wondered whether monitoring for multiple effector functions might reveal novel characteristics of effector CD8 T cells elicited by brief or prolonged Ag exposure. Using an in vitro system to generate effector T cells and an in vivo adoptive transfer model to track donor CD8 T cells, we found that the differentiation programs acquired by CD8 T cells after brief or prolonged antigenic stimulation were different. Although the frequencies of IFN-gamma and TNF-alpha producers were comparable for both effector CD8 T cell populations, there were major differences in cytotoxic potential and IL-2 production. Whereas prolonged (>24 h) Ag exposure stimulated effector CD8 T cells with high cytotoxic activity and low IL-2 production, brief (<24 h) stimulation generated effector CD8 T cells with low cytotoxic activity and high IL-2 production. The latter effector T cells rapidly converted into central memory-like CD8 T cells, exhibited long-term survival in adoptively transferred hosts, and gave robust recall responses upon Ag challenge. These data suggest that not all functions of effector CD8 T cells are equally inherited after brief or prolonged antigenic stimulation.     

The migration of lymphocytes into rat popliteal lymph nodes during antigenic promotion or competition between heterologous erythrocytes

The injection of chicken and sheep red blood cells (CRBC and SRBC) into rat popliteal lymph nodes either together or sequentially 2, 4, 6, or 8 days apart resulted in an enhanced immune response when the second antigen was injected 2 or 4 days after the injection of the first antigen (antigenic promotion) or a suppressed immune response when the second antigen was injected 6 days after the injection of the first antigen (antigenic competition). The immune response to either antigen was dependent upon the time of administration of the second antigen with respect to the first antigen. Lymphocyte migration into antigenically stimulated lymph nodes was greater when the two antigens were injected sequentially rather than together. Further, the migration of lymphocytes into the lymph node was enhanced when the second antigen was injected during the inductive or suppressive phase of the immune response to the first antigen (CRBC) regardless of whether the same (CRBC) or an antigenically unrelated antigen (SRBC) was used as the second antigen. While antigenic promotion may in part be explained by the increased rate at which lymphocytes migrate into lymph nodes, lymphocyte migration is also enhanced during antigenic competition. This suggests that while suppressor cells/factors may regulate the effector phase of an immune response they do not directly modulate the migration of blood-borne lymphocytes into the lymph node.     

Regulation of B cell responses to the variant surface glycoprotein (VSG) molecule in trypanosomiasis. I. Epitope specificity and idiotypic profile of monoclonal antibodies to the VSG of Trypanosoma brucei rhodesiense.

Regulatory mechanisms governing B cell responses to the trypanosome variant surface glycoprotein (VSG) molecule currently are being studied. As a fundamental basis for examining such regulation, the epitope specificities and idiotypic profiles of murine mAb produced to the VSG of Trypanosoma brucei rhodesiense clone LouTat 1.5 were determined. Variant specific mAb were used to probe VSG proteolytic peptides in Western blot analysis, to serve as competitive inhibitors in RIA analyses with purified VSG molecules, and to examine membrane-binding patterns of labeled trypanosome cells in order to evaluate epitope specificities. By using these approaches, a conformational epitope expressed only on the VSG 1.5 surface coat of viable trypanosomes was detected, and two nonconformationally determined epitope clusters were recognized within the subsurface V region of the VSG 1.5 molecule. The subsurface epitope clusters may be repeated on the VSG molecule because each was present on more than one proteolytic VSG peptide fragment. Idiotypic profiles of selected VSG-specific mAb subsequently were determined with xenogeneic antiidiotypic typing sera. Results from competitive inhibition RIA analyses using these reagents demonstrated that varying levels of idiotypic cross-reactivity exist among the subsurface VSG epitope-specific mAb; this cross-reactivity extended to idiotope(s) expressed by a mAb recognizing a surface conformational epitope of the VSG 1.5 molecule. Analysis of complementary idiotypic/antiidiotypic antibody pairs revealed that these specific interactions were inhibited by purified VSG 1.5 but not by purified VSG 1.9, which was derived from a heterologous variant antigenic type. The model mAb described here, and reagents recognizing their idiotypic markers, comprise a foundation for analysis of idiotypic regulation of VSG-specific B cell responses during infection.     

Regulation of the immune response to tumor antigen. VI. Differential specificities of suppressor T cells or their products and effector T cells.

Suppressor T cells arising during the development of certain murine methylcholanthrene-induced fibrosarcomas have previously been shown capable of limiting only those effector responses generated against the homologous tumor. Thus, S1509a-induced suppressor T cells inhibit immune reactivity only to the S1509a tumor in S1509a immune mice and have no effect on the rejection of SAI tumors in SAI-immune animals. In contrast to this is the cross-reactivity of effector cells in this system, whereby animals rendered immune to either the S1509a or SAI sarcoma are equally capable of rejecting a challenge of the opposite tumor. The specificity of suppression has been further defined in the present study, which demonstrates that S1509a-induced suppressor cells can inhibit responsiveness only to the S1509a sarcoma, even in the simultaneous presence of both the S1509a and SAI tumors. Furthermore, the suppressor factor that is obtainable from suppressor T cells demonstrates a similar precise specificity in its ability to limit selectively reactivity only against the inducing tumor, regardless of the simultaneous expression of antigens on other tumors recognized by cross-reactive effector cells. These results suggest that the antigenic determinants recognized by effector and suppressor T cells are different, and may provide a model for further dissection of suppressor cell function in vivo.     

Trypanosoma cruzi-induced suppression of IL-2 production. II. Evidence for a role for suppressor cells

Suppression of IL-2 production during experimental Chagas' disease accounts at least in part for the overall depressed state of the immune system in infected mice. The failure to produce IL-2 in response to mitogen stimulation is not the result of the lack of cells capable of producing IL-2, but appears to be due to regulation of IL-2 production by suppressor cells. This conclusion is supported by cell-mixing experiments where the ability of cells from infected mice to suppress normal spleen cell IL-2 production is evident. Although depletion of plastic and Sephadex G-10 adherent cells results in modest increases in IL-2 production by spleen cells from infected mice, even in the presence of normal adherent cells as a source of IL-1 producers, IL-2 production does not approach normal levels. Also, isolated macrophages are not by themselves suppressive for normal spleen cell IL-2 production, whereas plastic and G-10 nonadherent cells from infected mice are. Depletion of Thy-1+ and Ly-2+ cells not only completely abrogates the ability of spleen cells from infected mice to suppress normal IL-2 production, but results in a cell preparation which actually enhances IL-2 production. Anti-Ly-2 and C treatment of infected spleen cells also markedly enhances their ability to produce IL-2. These results indicate a major role for Ts cells in the regulation of IL-2 production, and a relatively minor role of macrophages as direct effector cells of suppression in this response. The ability to enhance IL-2 production in this system with PG synthesis inhibitors suggests a role for PG-producing cells such as macrophages in the suppressor mechanism, perhaps as inducers of the suppressor effector cells.     

Macrophage T lymphocyte interactions in the anti-tumor immune response: a mathematical model

In this paper we present a model of the macrophage T lymphocyte interactions that generate an anti-tumor immune response. The model specifies i) induction of cytotoxic T lymphocytes, ii) antigen presentation by macrophages, which leads to iii) activation of helper T cells, and iv) production of lymphoid factors, which induce a) cytotoxic macrophages, b) T lymphocyte proliferation, and c) an inflammation reaction. Tumor escape mechanisms (suppression, antigenic heterogeneity) have been deliberately omitted from the model. This research combines hitherto unrelated or even contradictory data within the range of behavior of one model. In the model behavior, helper T cells play a crucial role: Tumors that differ minimally in antigenicity (i.e., helper reactivity) can differ markedly in rejectability. Immunization yields protection against tumor doses that would otherwise be lethal, because it increases the number of helper T cells. The magnitude of the cytotoxic effector cell response depends on the time at which helper T cells become activated: early helper activity steeply increases the magnitude of the immune response. The type of cytotoxic effector cells that eradicates the tumor depends on tumor antigenicity: lowly antigenic tumors are attacked mainly by macrophages, whereas large highly antigenic tumors can be eradicated by cytotoxic T lymphocytes only.     

A qualitative study of an idiotypic cyclic network

Within the network hypothesis proposed by Jerne, the immune response is interpreted as a collective behaviour of different antibody species, interacting through idiotypic recognition. In order to insure the stability of the network, only a few species would be implied in the response to an antigenic challenge.We study a network made up of small cycles of idiotypic units, each element activating the subsequent one and repressing the preceding one. In the recent theoretical models, the kinetics is described by steep sigmoidal functions with a repression threshold lower than the stimulation one. To enable a systematic qualitative analysis of the dynamics, we replace the continuous kinetics by stepfunctions. The antibodies are thus considered as control elements like genes, enzymes or neurones. In order to account for the different thresholds, we use discrete three-level variables.We develop two methods to study the dynamics: the first one, due to Glass, describes the time-evolution of a cycle by a system of piecewise linear (PL) differential equations and the second method is the boolean formalization, applied extensively by Thomas in the field of genetic regulation.These techniques provide complementary informations about the dynamics of the cycle: the PL method establishes a state transition diagram providing all the potential behaviours independently of the parameter values in the model, whereas the purely logical analysis permits a simulation of the trajectories for precise values of the parameters.The state transition diagram presents several steady states. It suggests to interpret the response to an antigenic challenge as a transition from one steady state to another. The multiplicity of the steady states might be associated with the various modes of immune response depending on the doses of antigen injected and on the previous antigenic history of the system.     

Distinct profiles of human B cell effector cytokines: a role in immune regulation?

There is growing interest in the fundamental roles that B cells may play in regulating immune responses. Emerging animal studies point to an important contribution of B cell effector cytokines to immune modulation, yet little is known about the factors regulating such cytokine production. We report that the profile of human B cell cytokine production is context dependent, being critically influenced by the balance of signals through the B cell receptor and CD40. B cells appropriately stimulated by sequential B cell receptor and CD40 stimulation proliferate and secrete TNF-alpha, lymphotoxin, and IL-6, which can act not only as autocrine growth and differentiation factors, but also serve to amplify the ongoing immune response. In contrast, CD40 stimulation alone, a mimic of a B cell receiving bystander T cell help in the absence of specific Ag recognition, induces negligible proinflammatory cytokines, but significant production of IL-10 that serves to suppress inappropriate immune responses. We thus describe a novel paradigm of reciprocal regulation of B cell effector cytokines, and ascribe active roles for human B cells in either promoting or suppressing local immune responses through context-dependent cytokine production.     

Dynamics and comparative statics of mutualistic communities

Within the network hypothesis proposed by Jerne, the immune response is interpreted as a collective behaviour of different antibody species, interacting through idiotypic recognition. In order to insure the stability of the network, only a few species would be implied in the response to an antigenic challenge.We study a network made up of small cycles of idiotypic units, each element activating the subsequent one and repressing the preceding one. In the recent theoretical models, the kinetics is described by steep sigmoidal functions with a repression threshold lower than the stimulation one. To enable a systematic qualitative analysis of the dynamics, we replace the continuous kinetics by stepfunctions. The antibodies are thus considered as control elements like genes, enzymes or neurones. In order to account for the different thresholds, we use discrete three-level variables.We develop two methods to study the dynamics: the first one, due to Glass, describes the time-evolution of a cycle by a system of piecewise linear (PL) differential equations and the second method is the boolean formalization, applied extensively by Thomas in the field of genetic regulation.These techniques provide complementary informations about the dynamics of the cycle: the PL method establishes a state transition diagram providing all the potential behaviours independently of the parameter values in the model, whereas the purely logical analysis permits a simulation of the trajectories for precise values of the parameters.The state transition diagram presents several steady states. It suggests to interpret the response to an antigenic challenge as a transition from one steady state to another. The multiplicity of the steady states might be associated with the various modes of immune response depending on the doses of antigen injected and on the previous antigenic history of the system.     

Evidence for idiotypic- and antiidiotypic B-B cellular interaction with the use of cloned antiidiotypic B cell line

Immunization of BALB/c mice with MOPC104E myeloma protein induces antiidiotypic B lymphocytes that have Id-specific enhancing activity on antibody production. The B-B cell interaction was restricted to both Igh and class II MHC. However, anti-Thy-1 and C-treated splenic B cells were maintained for more than 1 y in a mixture of Con A-stimulated splenocyte culture supernatant and synthetic medium. In applying the long term culture method, we have established a cloned B cell line named B19-1d, B19-1d cells are specific to MOPC104E or J558 cross-reactive Id and they express surface mu, lambda but no Ly-1. B19-1d do not spontaneously secrete Ig but produce them upon stimulation with bacterial LPS. The effect of B19-1d cell line on idiotypic antibody production was tested. Addition of only 10 to 100 B19-1d cells into dextran-immune B cell culture greatly enhanced the Id+ antidextran antibody responses. On the contrary, the antidextran antibody production was suppressed by the higher doses of B19-1d cells. The effective cooperation between dextran-immune B cells and B19-1d cloned B cells was restricted to class II MHC. The role of idiotypic- and antiidiotypic B-B cell interaction in immune regulation and repertoire generation was suggested.     

TAP expression provides a general method for improving the recognition of malignant cells in vivo

A major class of tumors lack expression of the transporters associated with antigen processing (TAP). These proteins are essential for delivery of antigenic peptides into the lumen of the endoplasmic reticulum (ER) and subsequent assembly with nascent major histocompatibility complex (MHC) class I, which results in cell surface presentation of the trimeric complex to cytolytic T lymphocytes. Cytolytic T lymphocytes are major effector cells in immunosurveillance against tumors. Here we have tested the hypothesis that TAP downregulation in tumors allows immunosubversion of this effector mechanism, by establishing a model system to examine the role of TAP in vivo in restoring antigen presentation, immune recognition, and effects on malignancy of the TAP-deficient small-cell lung carcinoma, CMT.64. To test the potential of providing exogenous TAP in cancer therapies, we constructed a vaccinia virus (VV) containing the TAP1 gene and examined whether VV-TAP1 could reduce tumors in mice. The results demonstrate that TAP should be considered for inclusion in cancer therapies, as it is likely to provide a general method for increasing immune responses against tumors regardless of the antigenic complement of the tumor or the MHC haplotypes of the host.