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T cell glycoprotein CD4 binds to class II major histocompatibility molecules and to the human immunodeficiency virus (HIV) envelope protein gp120. Recombinant CD4 (rCD4) bound to polyclonal immunoglobulin (Ig) and 39 of 50 (78%) human myeloma proteins. This binding depended on the Fab and not the Fc portion of Ig and was independent of the light chain. Soluble rCD4, HIV gp120, and sulfated dextrans inhibited the CD4-Ig interaction. With the use of a panel of synthetic peptides, the region critical for binding to Ig was localized to amino acids 21 to 38 of the first extracellular domain of CD4. CD4-bound antibody (Ab) complexed with antigen approximately 100 times better than Ab alone. This activity may contribute to the Ab-mediated enhancement of cellular HIV interaction that appears to depend on a trimolecular complex of HIV, antibodies to gp120, and CD4.

Publisher Summary This chapter overviews the immune response. It describes problems, facts, and theories about antibodies when they are used as reagents. To determine how the immune system works, immunologists first use antibodies as reagents to identify and eliminate cells by virtue of unique antigens expressed on the cell surface. The idea of clonal selection, which is the underlying paradigm of modern immunology, is that the immune repertoire of an animal is formed by random rearrangements of roughly l0 4 gene segments. Inherent in the clonal selection paradigm is the counterintuitive notion of the pre-existence of a cell—containing the rearranged gene, encoding the specific antibody. Specificity is the property of reacting with the antigen against which the antibody is raised, and with no other antigen, but ultimately that distinction is one of technological limitations of the sensitivity of the assay. The affinity of the interaction between antigen and antibody is also an integral part of the challenge of specificity. Affinity is the strength of the interaction between the antigen and the antibody and can be measured as an affinity constant in those cases in which the antigen is in solution.

Any theoretical analysis of the immune system must make assumptions about its function. The almost universal assumption among immunologists is that the sole function of the system is to protect but over the past quarter century there have been occasional claims that the system also has generative functions. This paper puts the human immune response into an historical context to show that the protection that the system provides is primarily against opportunistic pathogens. Since humans organized themselves into societies until the end of the nineteenth century they have been subjected to continuous decimation by infectious agents, both as endemic disease and epidemics of catastrophic proportions. The changes in society brought about as a result of industrialization and the introduction of modern sanitation measures have been the primary reasons for the control of infectious diseases in the industrialized nations. The tragic lesson of the AIDS epidemic is that in the presence of adequate public health and antibiotics, the immune system is necessary for the defense against infections by opportunistic pathogens. It is of course possible that this is the sole function of the immune system, and if it is, theorists must be skeptical of data and conclusions from experiments designed with the large doses of highly antigenic material because these may not be examining the response as it functions in nature. Similarly, for reasons discussed in the paper, theorists and experimentalists should look to other functions of the immune system. These generative functions mayserve in growth and differentiation of the organism.

OKT3 is a murine monoclonal antibody directed against an epitope on one of the subunits of the CD3 complex on human T cells. CD3 is associated with the T cell receptor and seems to play a role in the expression of the receptor. Clinically it is used as rescue treatment in renal allograft rejection and is currently being tested for use prophylactically as a primary immunosuppressant. With success rates of ca 85 percent OKT3 has proven to be a successful and valuable addition to the clinicians armamentarium. However,a problem remains that can limit the use of OKT3 or any murine monoclonal antibody that is to be used in clinical practice. This is the problem of the production of anti-murine Ig antibody by the treated patient. These antibodies, which can be either anti-isotype or anti-idiotype (id) have the potential of preventing re-treatment with a murine monoclonal.

The induction of tolerance to the TNP hapten in populations of B cells in various states of differentiation was studied with the free, reactive hapten trinitrobenzene-sulfonic acid (TNBS). An adoptive transfer system was used in which tolerance was induced in an adoptively transferred B cell source before the addition of reconstituting thymus cells and immunization with hapten-carrier. Bone marrow cells and cells from fetal liver were rendered tolerant to TNP in this manner, showing that tolerance can be induced in cells from the primary B cell precursor and stem cell source of both the adult and fetal mouse. Tolerance was induced in normal spleen cells after adoptive transfer and in spleen cells from ATXBM mice (B cell spleens) after transfer to ATX hosts. These experiments show the induction of tolerance to TNP in B cells in another state of differentiation (peripheral B cells). Tolerance could be induced in B cell sources depleted of T cells indicating that immunologic tolerance to TNP may be induced in B cells in the absence of T cells. The possibility of residual TNBS affecting the thymus cells used for reconstitution was ruled out by transferring fetal liver cells to a secondary host after tolerance induction in a primary adoptive host, and also by rendering ATXBM mice tolerant before the transfer of their spleen cells to an adoptive host. These maneuvers remove the B cells from the environment used for tolerance induction, and indicate that TNBS did not act upon reconstituting thymus cells. The data indicate that tolerance to TNP can be induced in early differentiation states of the B cell.

Spleen and thymus cells of leukemic AKR mice suppress the in vitro anti-SRBC of normal spleen cells. We have demonstrated two types of leukemic cell suppression; a restricted suppression affecting only syngeneic or semi-allogeneic cells, and a nonrestricted suppression affecting both syngeneic and allogeneic cells. Restricted suppression is overcome by the presence of allogeneic cells, allogeneic supernates, or mitogens in the cultures. Nonrestricted suppression is not overcome by these factors. Restricted and nonrestricted suppression has been observed in two different leukemia systems; the Gross virus associated spontaneous leukemia of AKR mice and a Rauscher virus induced leukemia in B10.A mice. Although the leukemia is clonal, both restricted and nonrestricted suppressors have occasionally been found in the same mouse which may suggest that some modulation or selection of leukemic cell properties is occurring in response to specific host defense mechanisms.

All trans retinoic acid inhibited diferric transferrin reduction by HeLa cells. The NADH diferric transferrin reductase activity of isolated liver plasma membranes was also inhibited by retinoic acid. Retinol and retinyl acetate had very little effect. Transplasma membrane ferricyanide reduction by HeLa cells and NADH ferricyanide reductase of liver plasma membrane was also inhibited by retinoic acid, therefore the inhibition was in the electron transport system and not at the transferrin receptor. Since the transmembrane electron transport has been shown to stimulate cell growth, the growth inhibition by retinoic acid thus may be based on inhibition of the NADH diferric transferrin reductase.

Suppression of in vitro antibody forming potential of normal cells by leukemic cells of AKR and normal neonatal mice have many similarities. In both cases the suppression is by cell contact rather than by the elaboration of soluble suppressive factors and the suppression is sensitive to both x-irradiation and mitomycin C treatment. When the size distribution of suppressing cells in thymus and spleen were compared by velocity sedimentation, both leukemic and neonatal suppressing cells had similar size distribution in each organ. Both large and small cells in the thymus suppress but only large cells (sedimentation velocity >3.5 mm/hr) in the spleen are able to suppress. Leukemic cells in lymph node have a splenic size distribution, viz., only large cells suppress. Both large and small cells of a subcutaneously growing long passage AKR lymphoma are able to suppress. While large cells contain the bulk of cells actively incorporating tritiated thymidine and thus probably in cycle, small but significant amounts of incorporation in small suppressing cells is also seen.

Pretreatment of mice with a suboptimal immunizing dose of SRBC (106) prepares the animals to make an “accelerated” response to an optimal immunizing dose of SRBC (108) given two or more days later. The “accelerated” response is characterized by a shift to the left of the kinetic curves when the number of antibody forming cells are plotted against time. The response to the 108 SRBC thus reaches a peak earlier in the pretreated animals than in the nonpretreated controls. The slopes of the kinetic curves are parallel and the magnitude of the response is not significantly different in pretreated and nonpretreated groups. Multiple injections of 106 SRBC give a greater “accelerated” response but one injection with the total dose of the multiple injections results in kinetics similar to those obtained with the single 106 dose. The response is antigen specific. It is suggested that the basis of the “accelerated” response is proliferation of a cellular component(s) without differentiation into an antibody forming cell.

Summary Injection of isolated polymorphonuclear neutrophil (PMN) granules into the skin of normal rabbits causes a local leukocytosis and increase in vascular permeability. The permeability increase is dose dependent and maximal at 2 hr. Activity is not affected by dialysis but is almost completely lost after heating at 85°C for 30 min. The granule preparations do not cause contraction of an isolated segment of smooth muscle nor are they affected by doses of cyproheptidine which inhibit the action of histamine and serotonin. Pretreatment of normal recipient rabbits with 5 mg/kg body weight of cortisone-acetate abolishes the vascular response to intact granules, but not lysed granules. It is concluded that cortisone prevents in vivo lysis of the granule by membrane stabilization. All of the permeability increasing properties were located in the 20% ethanol precipitable fraction of PMN granules. This fraction was shown to contain little cathepsin-like protease activity. The majority of the cathepsins were located in the 45 and 80% ethanol precipitable fractions. The active fraction was found by electrophoresis to be the most cationic. The vascular permeability increasing activity of intact or lysed granule preparations was not reduced by the general protease inhibitors phenylmethylsulphonyl fluoride or soybean trypsin inhibitor. It was concluded that the vascular permeability altering properties of PMN granules might not be due to the presence of the cathepsins. The possibility that activity is due to electrostatic charge is presented. The histology of the granule-induced lesions is similar to the histology of the Arthus reaction. There is edema, an accumulation of PMN and vasculitis in both cases, but the granule induced histologic alterations appear at an earlier time after injection than do comparable changes in the Arthus reaction. A possible mechanism for the Arthus reaction is presented.

Treatment of mice with a nonimmunogenic preparation of free reactive hapten, trinitrobenzene sulfonic acid (TNBS), leads to the induction of a state of tolerance to the hapten, 2,4,6-trinitrophenyl (TNP). This is determined by the lack of response to the haptenic moiety in an immunogenic hapten-carrier conjugate (TNP-SRBC) as assayed both by serum antibody titrations and the hemolytic plaque assay. The tolerance produced is specific for the hapten, since the anticarrier responses are essentially unaltered compared with the control values. The unresponsiveness induced by TNBS treatment is a dose-dependent phenomenon, becoming less complete at lower doses of TNBS. The tolerance is of a definite length, both in its induction phase and in the duration of the established unresponsive state. Tolerance can be maintained and extended, and may also be reentered once escape has been initiated.

Summary The variation in the dose of ultracentrifuged human γ globulin (HGG) needed to produce an unresponsive state in different strains of inbred mice was shown to be the result of differences in the efficiency with which these strains process the trace amount of aggregated material remaining. Although mice from both C57BL/6J and BALB/cJ strains remove the aggregated material from the vascular fluids following injection of HGG, the BALB/cJ mice appear to process this material efficiently, and an immune response rather than an unresponsive state results. Conversely, C57BL/6J mice appear to process the aggregated material inefficiently, thus permitting the induction of unresponsiveness to the non-aggregated (tolerogenic) material. When the trace amount of aggregates was removed by salt fractionation, mice from both strains became unresponsive to small doses of HGG. The tolerogenic, deaggregated HGG was rendered immunogenic by chemical aggregation. The dose of HGG to which mice become unresponsive appears to be controlled by a genetic mechanism involving more than one gene. C57BL/6J mice readily became unresponsive following injections of deaggregated γG isolated from normal rabbit serum, but made an antibody response to γG (ALG) isolated from the sera of rabbits immunized with mouse thymus cells. Mice made unresponsive to deaggregated RγG did not lose their unresponsive state following injection of ALG. Within the limits of the test system that was used, no low-dose unresponsive state was observed in C57BL/6J and BALB/cJ mice injected with ultracentrifuged HGG.

A single injection of trinitrobenzenesulfonic acid (TNBS) induces a state of immunologic tolerance to the trinitrophenyl (TNP) hapten, which is specific and dose dependent. multiple injections of TNBS induce a longer lasting state of unresponsiveness than single injections. Escape from tolerance is characterized by the production of only 2-mercaptoethanol (ME)-sensitive (19S) anti-TNP antibody whether tolerance is induced by single or multiple injections. multiple injections of hapten-carrier conjugate (TNP-sheep erythrocytes) extend the duration of the tolerance induced by multiple injections of TNBS. The anti-TNP response of animals escaping from tolerance induced by multiple TNBS injections and extended by multiple hapten-carrier challenges consisted entirely of ME-sensitive (19S) antibody. Substitution of carrier for hapten-carrier conjugate in the initial challenge injection resulted in a normal anti-TNP response pattern in terms of class and temporal sequence of antibody produced during escape from tolerance. TNBS treatment had no effect upon the “accelerated” response to carrier induced by low-dose carrier priming, and TNBS treatment induced tolerance to TNP in low-dose carrier-primed mice.

Young CBA spleen cells respond initially to sheep red blood cells (SRBC) in vitro at 15 days of age but the response is less than 10% of the adult response. The magnitude of the response reaches levels comparable to those in the adult at 7 weeks of age. Spleen cells of 1-week-old mice can reconstitute the anti-SRBC response of lethally x-irradiated adult mice but cannot respond to SRBC when placed in diffusion chambers implanted in the peritoneal cavity of sub-lethally irradiated adult syngeneic recipients. In an attempt to determine the cellular basis of the “immunologic immaturity,” reciprocal recombinations of adult and young macrophage-rich adherent (A) cells and lymphocyte-rich non-adherent (NA) cells were made. It was found that young A cells are functional, but young NA cells are not. The implications of these findings in terms of the mechanism of maturation and the acquisition of immunocompetence by the young mouse are discussed. It is suggested that the cause of incompetence in the young spleen cells is the presence of pluripotent stem cells but not of committed lymphoid precursors. This may be due to the lack of functional lymphocyte-directed-inducing-microenvironments which would induce stem cells to differentiate into committed lymphoid precursors.

Immunization of rabbits with mouse brain (which is known to contain Θ antigen) results in a potent anti-Θ-like antiserum. This antiserum termed “anti-brain-associated Θ”, BAΘ, is cytotoxic to thymus cells but not marrow cells, inhibits the primary in vitro response to RBC, does not affect antibody-forming cells which are of marrow origin, and inhibits the graft-versus-host reaction. It serves as a convenient means of obtaining large quantities of anti-thymus antiserum.

Summary A method is presented which allows the in vitro enumeration of cells producing antibody against a variety of protein antigens. The proteins are covalently linked to red blood cells by means of a carbodiimide reagent. The concentrations of protein required for the plaque assay are greater than those required for passive agglutination. The method is simple and sensitive and the results mimic the kinetics of the response that is seen in in vivo assays of serum antibody. Both direct (probably 19 S) and indirect (probably 7 S) plaque-producing cells are detected.

The functional ontogeny of the interacting T cell and B cell4 populations in the antibody response to sheep erythrocytes (SRBC) was investigated in CBA mice. It was found that T cell function, as determined by the ability of test cells to interact with adult bone marrow cells, was not detectable in fetal or neonate liver or lung. Moreover, even in the thymus this function remained less than 10% of adult values until birth. At birth T cell function increased exponentially, reaching adult levels within 48 hr. Neonatally thymectomized mice reconstituted with thymus cells of various ages confirmed these results. By day 4 after birth, T cell function could be detected in the spleen. B cell function, as determined by the ability of test cells to interact with adult thymus cells, was detected in the neonate spleen from day one. Therefore, both B cell and T cell function was present in the spleen from day 4 after birth. B cell function also was found in the fetal and neonate liver. B cell function of fetal liver was only 1/6 that of adult bone marrow on fetal day 16, quickly surpassed adult bone marrow activity near birth, and then equalled adult bone marrow activity until day 6 after birth. The ontogeny of B cell and T cell function in the antibody response to SRBC appears to take place at separate times in the mouse. B cell function develops first, most probably from the most primitive stem cell. T cell function develops later, after a structural thymus is present. Migration of T cell lymphocytes to other lymphoid tissue shortly after birth is consistent with the data presented.

θ is a mouse alloantigen which serves as a marker for thymus-derived (T) cells (1). Anti-θ antisera have proven to be powerful tools in elucidating the roles of bone marrow-derived (B) and T lymphocytes (2). θ is shared by T lymphocytes and brain tissue in the mouse (1). We had previously shown (3) that immunization of rabbits and goats with mouse brain results in the production of potent anti-θ-like antisera. We have termed these anti-brain-associated θ antisera (BAθ). It would be a great advantage in studying immune systems other than the mouse if antigen comparable to θ were available. We have taken a variety of approaches in an attempt to develop anti-θ-like antisera to other species. One of these is to investigate brain tissue of other species to determine if it contains cross-reacting antigens with mouse BAθ.

In den vorangegangenen Kapiteln haben wir die Funktionen der einzelnen Lymphozytenpopulationen bei der Antikorperbildung und bei zellvermittelten Reaktionen beschrieben. Jetzt wollen wir naher darauf eingehen, welche Bedeutung das Antigen fur die Wechselwirkung zwischen den Zellen bei der Immunantwort hat. Die vom Thymus abstammenden und die vom Knochenmark abstammenden Zellen reagieren jeweils mit unterschiedlichen antigenen Determinanten auf dem Antigenmolekul, dem Hapten und dem Carrier. Die B-Zellen reagieren nur mit den Hapten-Determinanten und die T -Zellen nur mit den Carrier-Determinanten. Da bei der Antikorperbildung die B-Zellen die Effektor-Zellen darstellen und die T -Zellen als Helfer-Zellen fungieren, kann man die Carrier-Determinante, mit der die T-Zelle reagiert, als Helfer-Determinante auffassen. Die B-Zelle reagiert mit der Hapten- Determinante und bildet gegen sie den Antikorper. Das Antigenmolekul mus dementsprechend zwei antigene Strukturen besitzen, den Carrier-Teil fur die T -Zelle und den Hapten-Teil fur die B-Zelle.

Wir haben bereits die Kettenstruktur und die antigenen Eigenschaften der Ig-Molekule besprochen und mochten uns nun Untersuchungen uber die Struktur der Antikorper-Bindungsstelle zuwenden, die ein besseres Verstandnis der spezifischen Bindung mit dem Antigen ermoglichen sollen. Die Hund L-Ketten des Ig-Molekuls konnen in die variablen und konstanten Regionen eingeteilt werden. Die enorme Vielfalt unterschiedlicher Aminosaurenfrequenzen in den variablen Regionen ermoglicht ein weiteres Spektrum unterschiedlicher Antigenbindungsstellen. Wir werden in diesem Kapitel beschreiben, wie die Fragen nach der strukturellen Basis der Antikorperspezifitat angegangen und gelost wurden.

Im letzten Kapitel wurde der Einflus einer neonatalen Thymektomie und neonatalen Bursektomie auf die Immunantwort besprochen. Nach der neonatalen Thymektomie kann ein Tier weder Antikorper bilden noch ein Transplantat abstosen. Nach der Bursektomie ist jedoch nur die Antikorperbildung gestort, der Mechanismus der Transplantatabstosung bleibt erhalten. Bei der Antikorperbildung sind die von der Bursa abstammenden Lymphozyten (die B-Zellen) die Effektorzellen, d.h. die Antikorper-produzierenden Zellen. Die vom Thymus abstammenden Lymphozyten (die T -Zellen) wirken bei der Antikorperbildung nur als „Helfer-Zellen“. Wie an der Antikorperbildung, so sind auch an zellvermittelten Immunreaktionen verschiedene Lymphozytenpopulationen beteiligt, wobei ein ahnliches Verhaltnis zwischen Effektor- und Helfer-Zellen besteht. Bei den zellvermittelten Reaktionen sind jedoch sowohl die Effektor als auch die Helfer-Zellen T-Zellen.

might encode secreted forms of the class I molecule. Transfection experiments should help to clarify these questions and to determine what fraction of the class I genes are pseudogenes. Obviously some of the class I genes may encode differentiation antigens in addition to the TL and Qa antigens that, accordingly, may have been difficult to detect by conventional serological approaches. There is a possibility that the genes for class I molecules may employ alternative RNA-splicing patterns to generate two or more polypeptides from the same gene, as is seen with the heavy-chain genes for immunoglobulins, which generate the membrane and secreted molecules by a similar mechanism. Several indirect lines of evidence suggest that the multiple exons and introns encoding the cytoplasmic domain may be involved in alternative RNA-splicing patterns that would result in the synthesis of distinct transplantation antigens with the same external domains and different cytoplasmic domains (Steinmetz et al., Cell 25, 683-692, 1981).

Bestimmte Subpopulationen von Lymphozyten mit unterschiedlicher Funktion reagieren mit ganz bestimmten Determinanten des Antigenmolekuls. Um eine Immunantwort hervorzubringen, mussen diese Subpopulationen mit Makrophagen interagieren. Die Mechanismen der zellularen Interaktionen bei der Immunantwort sollen in diesem Kapitel naher untersucht werden. Diese Beobachtung, die vor 10 Jahren grose Uberraschung ausloste, hat inzwischen zu der Vorstellung von Zellinteraktionsmolekulen (cell interaction moleculs = CI) gefuhrt, d. h. von Molekulen, die von Genen des H-2-Komplexes kodiert sind und die es durch ihre Struktur den Zellen ermoglichen, in Wechselwirkung zu treten. Es werden zwei alternative Mechanismen fur die CI-Molekul-Interaktion diskutiert, und zwar einmal eine Interaktion zwischen gleichen Molekulen oder aber eine Interaktion uber ein ,,Akzeptor“-Molekul auf einer Zelle. Untersuchungen von Knochenmarkchimaren stellten dann jedoch in Frage, das Histokompatibilitat tatsachlich eine Voraussetzung fur Zellkooperation darstellt. Daraus entwikkelte sich die Vorstellung einer „adaptiven Differenzierung“. Dieser Begriff besagt, das sich CI-Molekule an einen anderen H-2-Typ adaptieren, wenn sie sich im Milieu des anderen H-2-Typs differenzieren. T-Zellen haben Rezeptoren fur eigene H-2-Antigene und mussen sowohl mit dem eigenen H-2-Antigen auf dem Makrophagen als auch mit dem Fremdantigen reagieren, urn bei Antikorper-Antworten wirksam zu werden. Dies wurde aus folgenden Beobachtungen geschlossen: T-Zellen und Makrophagen mussen gemeinsame MHC-Antigene besitzen, damit die T -Zellen durch Antigen aktiviert werden konnen. F1-Tiere besitzen zwei Typen von T-Zellen, von denen jeder mit den Molekulen eines elterlichen Haplotyp reagiert. Die Reaktion der T-Zelle mit den eigenen MHC-Antigenen auf den Makrophagen fuhrt zu klonaler Vermehrung der Zellen, die Rezeptoren fur eigene MHC-Antigene tragen. Wenn die T-Zelle auf Antigen trifft, reagiert sie sowohl mit dem Antigen als auch mit MHC-Antigenen auf Makrophagen. Diese Autoreaktivitat ist Voraussetzung fur Reaktionen gegen Fremdantigen.

Entfernt man einem Tier die primaren lymphatischen Organe (Thymus und Bursa), so kommt es zu Storungen der Immunantwort: ein Tier ist nicht mehr fahig, Antikorper- und zellvermittelte Immunreaktionen hervorzubringen, wenn ihm unmittelbar nach der Geburt der Thymus entfernt wurde (neonatale Thymektomie). Nach neonataler Bursektomie kommt es bei Vogeln nur zu einem Verlust der Antikorperbildung. Letal bestrahlte Mause konnen nur dann wieder Antikorper bilden, wenn ihnen gleichzeitig Knochenmark- und Thymuszellen injiziert werden, nicht jedoch wenn sie nur Thymuszellen oder Knochenmarkzellen erhalten. Daraus folgt, das eine „Arbeitsteilung“ unter den Lymphozyten vorliegt, das jedoch eine Kooperation zwischen ihnen notwendig ist, damit es zur Immunreaktion kommt. Thymuszellen, die in neonatal thymektomierte Mause injiziert werden, produzieren keine Antikorper, sie befahigen jedoch in der Empfangermaus bereits vorhandene Zellen zur Antikorperbildung. Durch Rekonstitutionsexperimente mit Knochenmark- und Thymuszellen wurde nachgewiesen, das die Lymphozyten aus dem Knochenmark zu Antikorper-produzierenden Zellen werden, wahrend die Zellen aus dem Thymus als „Helfer“-Zellen wirken.

Man schatzt die Anzahl der Antikorperspezifitaten, die ein Lebewesen bilden kann, auf ungefahr 106. Die grose Zahl verschiedener Antikorpermolekule, von denen jedes spezifisch mit einem Antigen reagiert, stellt eine erstaunliche Leistung des Immunsystems dar. Im folgenden wollen wir nun Mechanismen darstellen, die diese Vielfalt ermoglichen. Gleichzeitig warden wir diskutieren, wie trotz dieser Vielfalt eine so weitgehende strukturelle Ubereinstimmung zwischen den einzelnen Antikorpermolekulen moglich ist.

Die lymphatische Progenitorzelle differenziert unter dem Einflus von hormonahnlichen Faktoren in den primaren lymphatischen Organen, dem Thymus und der Bursa. Aus diesen primaren lymphatischen Organen wander die Lymphozyten aus und entwickeln sich in den sekundaren lymphatischen Geweben zu funktionellen B-Zellen oder T-Zellen. Wie in Kapitel 3 und 4 beschrieben, reagieren die funktionellen Lymphozyten mit Antigen und kooperieren hierbei untereinander. Im folgenden sollen nun charakteristische Eigenschaften von B-Zellen und T-Zellen beschrieben werden.

In diesem Kapitel werden wir besprechen, das die Zellen des Blutes (Erythrozyten, Granulozyten und Lymphozyten) trotz ihrer unterschiedlichen Morphologie und Funktion von einer gemeinsamen Urzelle abstammen. Alle Zellen des Blutes entwickeln sich aus einer pluripotenten Stammzelle uber eine Progenitorzelle und eine Vorlauferzelle zur funktionellen Zelle. Die Differenzierung einer Progenitorzelle zu einer Vorlauferzelle findet in bestimmten Mikromilieus statt. Der Thymus und die Bursa (bzw. ihr Aquivalent bei Saugetieren) bilden das Mikromilieu zur Differenzierung der lymphatischen Zellen und werden deshalb primare lymphatische Organe genannt. Von diesen primaren lymphatischen Organen wandem die Lymphozyten aus und gelangen zu den peripheren oder sekundaren lymphatischen Organen, Milz und Lymphknoten.

Bone marrow contains pluripotent stem cells which give rise to colonies when injected into irradiated syngenic hosts as well as more differentiated progenitor cells of the myeloid cell which are able to form colonies in vitro. Antisera against brain is known to contain antistem cell antibody. The present experiments were designed to determine if the myeloid progenitor cell still expresses the stem cell antigen. Bone marrow cells were treated with antibrain antiserum plus complement and then survival of stem cells was determined by injection into irradiated hosts. Survival of myeloid progenitor cells was determined by culturing the cells in vitro. It was found that stem cells were eliminated by the antiserum but that myeloid progenitors were not. Inefficient in vitro lysis was ruled out as the reason for this difference since in vitro colonies were not reduced when the cells were treated with anti-immunoglobulin or after passage through an irradiated host. In the differentiation from stem cell to myeloid progenitor there is an associated surface antigen change.

Das Wesen der Immunantwort besteht darin, das eine kleine Zahl von Vorlauferzellen aktiviert wird, die sich zu einer Population von funktionellen Effektorzellen vermehren. In diesem Kapitel beschreiben wir, wie Antigen die Proliferation von den Zellen induziert, die dazu bestimmt sind, auf dieses Antigen spezifisch zu reagieren. Im Verlauf einer Immunantwort kommt es also zu einer klonalen Vermehrung von Zellen mit einer bestimmten spezifischen Antigenreaktivitat. Die Eigenschaften der von den B-Zellen gebildeten Antikorper verandern sich ebenfalls im Verlauf einer Immunantwort. Wahrend der Primarantwort werden zuerst IgM-Antikorper gebildet, aber im weiteren Verlauf der Primarantwort kommt es zu einem Wechsel („shift“) zu IgG. In der Sekundarantwort werden fast ausschlieslich IgGAntikorper produziert. Auserdem kommt es innerhalb der 7 S-AntikorperMolekule auch zu einer Anderung der Bindungsaffinitat. Dies ist darauf zuruckzufuhren, das das Antigen zu einer Selektion von Zellen fuhrt, die Antikorper mit hoher Affinitat produzieren. Diese Zellen reagieren bevorzugt mit dem Antigen, das deshalb bevorzugt bei ihnen eine Proliferation induziert. Auf diese Art selektioniert das Antigen also die Proliferation von Zellen mit spezifischen Antigen-Bindungsrezeptoren. Innerhalb der Zellen mit spezifischen Antigen-Bindungsrezeptoten besteht ein Selektionsvorteil fur die Zellen, die Rezeptoren mit hoher Affinitat haben.

Das Produkt der B-Zelle ist das Antikorpermolekul. Antikorpermolekule finden sich in der Globulinfraktion des Serums und werden deshalb Immunglobuline genannt. In diesem Kapitel werden wir beschreiben, das Immunglobuline aus vier Einzelketten aufgebaut sind. Die Antigen-bindende Region ist an einem Ende des Molekuls lokalisiert, am anderen Ende befindet sich die strukturelle Grundlage fur die Fahigkeit, Komplement zu binden und andere biologische Funktionen zu ubemehmen. Ig-Molekule sind heterogen. Ihre antigene Heterogenitat (d. h. ihre Fahigkeit, in einer anderen Spezies selbst als Antigen zu wirken und die Bildung unterschiedlicher Anti-korper zu induzieren) ermoglicht eine Klassifizierung. Alle Mitglieder einer Spezies haben samtliche Immunglobulinklassen. Innerhalb einer Spezies gibt es eine weitere Heterogenitat, die ebenfalls genetisch determiniert ist. Sie wird allotypische Variation genannt. Der individuelle Charakter der antigenen Bindungsstelle einzelner Antikorpermolekule bedingt eine weitere Heterogenitat, die man idiotypische Variation nennt. In diesem Kapitel wollen wir nun auf einige Besonderheiten der Struktur und der Heterogenitat der Immunglobuline eingehen.

Das charakteristische Merkmal des Immunglobulinmolekuls ist seine Fahigkeit, Antigen spezifisch zu binden. Immunglobuline haben allerdings auch noch andere biologische Eigenschaften, die wir in diesem Kapitel naher beschreiben wollen.

Der MHC spielt eine entscheidende Rolle bei der Entstehung von Antikorperreaktionen, da er die Aktivierung von T -Zellen durch Antigen beeinfludast. Der Mechanismus dieser Aktivierung beinhaltet wahrscheinlich die Interaktion von Ia-Antigenen auf Makrophagen mit anti-Ia-Rezeptoren auf T-Zellen.

In den vorangegangenen Kapiteln haben wir beschrieben, wie die MHCRestriktion bei der Aktivierung von Helfer-T-Zellen fur die Antikorperbildung und auch bei der Entstehung zytotoxischer T -Zellen nachgewiesen wurde. Im folgenden wollen wir uns einem weniger gut verstandenen Bereich zuwenden, namlich der Frage, wie aktivierte T -Zellen den Effektor-B-Zellen Hilfe vermitteln. Dabei wird die Analyse der Antikorperbildung im Mittelpunkt stehen, da sie sehr viel ausfuhrlicher untersucht wurde als zellvermittelte Reaktionen. Es wird sich zeigen, das sich zur Erklurung der experimentellen Beobachtungen sowohl Modelle eignen, bei denen die Hilfe fur die B-Zellen durch Zellkontakte vermittelt wird, als auch solche, die von loslichen Faktoren ausgehen. Bei den letzteren kann man solche mit Antigenspezifischen Faktoren von anderen mit Antigen-unspezifischen Faktoren unterscheiden. Welche Rolle diese Faktoren oder auch die MHC-Restriktion bei der Verwirklichung der Hilfe wirklich spielen, ist unbekannt.

Cells which are self renewing and whose progeny have the potential of establishing more than one lineage are called stem cells. When stem cells are induced to differentiate they lose their multipotency and establish lineages leading to the development of functional end cells. Of the many differentiating systems which use the strategy of the stem cell (1,2), the hemopoietic system is one of the more intensely studied because the process occurs continuously in the adult animal (see ref 3). The cells of the blood arise from multipotent hemopoietic stem cells which give rise to progenitor cells of committed lineage. The granulocyte-macrophage progenitor cell has at least one more lineage establishment decision to make in the progression toward functional end cells and can be used as a model for decision making in lineage establishment.