The Journal of Experimental Medicine

Malt, Ronald A.; Miller, Walter L.

doi: 10.1084/jem.126.1.1pmid: 6027645

The synthesis of nuclear precursors of rRNA and of cytoplasmic mRNA has been estimated in mouse kidneys following contralateral nephrectomy. 1. The production of nuclear rRNA parallels mitotic activity in the proximal tubule cells. Its peak is 2 days after nephrectomy; there may be a second peak at 8 days. 2. The production of mRNA is almost the reciprocal of rRNA production. It is least at 2 days and most at 4 days after nephrectomy. It may also decrease immediately after nephrectomy. 3. Growing kidney cells may build a store of ribosomes before they elaborate mRNA. The sequential relation between rRNA and mRNA synthesis raises the possibility that production of rRNA could regulate the production of mRNA and that the stimulus to compensatory hypertrophy might need to act only long enough to set into motion the machinery for making rRNA, either directly or as a consequence of exhausting mRNA. Footnotes Submitted: 15 January 1967

Eidinger, David; Pross, Hugh F.

doi: 10.1084/jem.126.1.15pmid: 6027644

The direct and indirect plaque technique for the detection of antibody-forming cells against sheep erythrocytes was utilized for the investigation of a number of biological parameters of the primary and secondary immune response on a cellular level. The sequential pattern of 19S followed by 7S antibody formation was elicited in the primary response after a latent period of at least 1–2 days and 2–3 days respectively. The secondary response initiated 140 days after primary immunization, in contrast, was characterized by the simultaneous appearance of 19S and 7S antibody-forming cells after an observed latent period of 2–3 days. The cellular dynamics of the recruitment phase of the respective immunoglobulins in the primary and secondary response was interpreted as evidence for the derivation of the two classes of immunoglobulins from separate progenitors. The 19S antibody-forming cells were derived predominantly by a process of transformation and maturation and 7S antibody formers by a process of cellular division with a doubling time of about 12 hr. The draining lymph node exhibited maximal immunological reactivity due to its capacity to retain the particulate antigen. This capacity was considerably enhanced in the sensitized draining lymph node. Minimal cellular activity was also noted in distal lymphoid tissues which included the thymus. Focal cellular activity was observed in the draining lymph node for 60 days after immunization. Subsequently, very low level plaque-forming cellular activity was observed in association with persistence of maximal antibody activity. The appearance at 120 days of a generalized peak of cellular activity in lymphoid tissues throughout the host was considered an explanation for this discrepancy. The change in distribution of cellular antibody-forming activity, from a local to a generalized lymphatic response during the late phase of the immune response, implied a fundamental alteration in homeostatic mechanisms associated with maintenance of immune reactivity. Further manifestations of such an alteration were indicated by the appearance of 2-ME-sensitive 7S antibody nearly 3 months after primary intradermal immunization, which in the ensuing 5 months was associated with, and inversely related to, two major fluctuations in 2-ME-resistant 7S antibody. Evidence for the existence of immunological memory in the 19S system was not established in the present work. 19S anamnesis, for which evidence was derived from measurements of circulating antibody levels, was interpreted from cellular studies as the result of the substantial activity of previously uncommitted 19S lymphoid cells in distal lymphoid tissue associated with previously committed 19S cells contained in the draining lymph node. Footnotes Submitted: 25 January 1967

Hall, C. E.; Holland, O. B.; Hall, O.

doi: 10.1084/jem.126.1.35pmid: 6027646

Adrenal-enucleated, mononephrectomized rats given a high salt diet rapidly develop malignant hypertension, characterized by the presence of necrotizing vascular lesions in a number of organs and tissues. If a normal salt intake is provided, or if hydrochlorothiazide is given together with a high salt diet, there is, instead, the delayed onset of benign hypertension which either stabilizes or increases in intensity extremely slowly; Such animals display few, if any, pathologic vascular changes other than occasional focal glomerular hyalinization, show insignificant cardiac enlargement, and do not exhibit alterations in the serum sodium or potassium. Occasional animals behave atypically and develop malignant hypertension despite normal salt consumption, demonstrating that in susceptible rats excess salt is not essential to this disorder. Hydrochlorothiazide given to rats that imbibed distilled water postoperatively prevented hypertension entirely for 97 days, when one of eight rats developed mild hypertension and some others reached what is regarded as a prehypertensive range. It is concluded that adrenal regeneration provides a physiological milieu favorable to the development of benign hypertension, which is not, as a rule, manifest until regeneration is complete. Salt excess converts the response into one in which malignant hypertension begins during regeneration and worsens rapidly thereafter until death. The course and findings are compared with those of the benign and malignant phases of clinical essential hypertension, and the implications of the similarities are discussed. Footnotes Submitted: 26 January 1967

Mellors, Robert C.; Huang, Chen Ya

doi: 10.1084/jem.126.1.53pmid: 6027647

Hemolytic disease characterized by slight anemia, reticulocytosis, hemosiderosis, extramedullary hematopoiesis, and positive indirect antiglobulin (Coombs') tests and renal disease with proteinuria, hypoalbuminemia, and glomerular lesions were produced in Swiss mice by neonatal intraperitoneal inoculation of cell-free filtrates prepared from the spleens of old NZB/Bl mice. Lymphoid cell and plasma cell hyperplasia as well as hypergammaglobulinemia occurred in some of these inoculated mice. Type "C" murine oncogenic virus-like particles, indistinguishable from those previously described (1), were shown by electron microscopic study to be present in distinctive locations, notably in the basal foldings of convoluted tubules in the kidneys of a newborn NZB/Bl mouse, old NZB/Bl mice, a CBA x NZB F 1 hybrid mouse, and a Swiss mouse inoculated with NZB/Bl spleen cell-free filtrate. These observations point to two (perhaps related) circumstances which may be requisites for the pathogenic action of this newly discovered virus within and outside the strain NZB: infection of newborn, or infant, mice; persistent, possibly tolerant, infection of adult mice. Footnotes Submitted: 7 February 1967

Rudbach, Jon A.; Milner, Kelsey C.; Ribi, Edgar

doi: 10.1084/jem.126.1.63pmid: 4961269

When endotoxins extracted from enteric bacteria were mixed in the presence of sodium deoxycholate, and the bile salt was subsequently removed by dialysis or by extraction with ethanol, a new type of endotoxin was formed. The latter material was as biologically active as the original endotoxins and possessed a combination of antigenic determinants that were previously unique to each of the individual endotoxins in the mixture. This hybrid formation between endotoxins was detected by immunodiffusion and radioautography and by quantitative precipitation procedures. Footnotes Submitted: 2 March 1967

Brody, Neil I.; Walker, J. Geoffrey; Siskind, Gregory W.

doi: 10.1084/jem.126.1.81pmid: 4165502

In the system studied, antigenic competition between two haptenic determinants was found to be of the same extent whether the haptens were on the same or on separate carrier molecules. Suppression of antibody formation to one determinant by administration of passive antibody partially eliminated the depressive effects of antigenic competition when the two haptens were located on separate carrier molecules but had no effect on antibody production to the second hapten when the two determinants were present on the same molecule. The results are discussed in terms of the mechanisms of suppression, antigenic competition, and control of antibody formation. Footnotes Submitted: 5 March 1967

Lindenmann, Jean; Klein, Paul A.

doi: 10.1084/jem.126.1.93pmid: 4290961

A2G mice could be solidly immunized against the Ehrlich ascites tumor by single intraperitoneal injections of homogenized and lyophilized tumor cells which had been infected with oncolytic strains of influenza A virus. Similar homogenates from noninfected tumor cells were not immunogenic, even when mixed with egg-grown virus. The immunizing principle in viral oncolysates could not be separated from the oncolytic virus by differential centrifugation or adsorption to and elution from red cells. It could be inhibited by antibody raised in rabbits against the egg-grown oncolytic virus. This reaction showed serologic specificity. Thus, the immunogenicity of an oncolysate produced with the WSA strain of neurotropic influenza virus could be inhibited by rabbit anti-WSA, but not by rabbit antibody to the TUR strain of fowl plague virus. Conversely, the immunogenicity of an oncolysate prepared with the TUR strain could be inhibited by rabbit anti-TUR, but not by anti-WSA. When mice were preimmunized (primed) with egg-grown WSA virus, their antitumor response to a later injection of WSA oncolysate was of the anamnestic type. Priming with egg-grown influenza B virus had no such effect. It was concluded that the immunogenicity of certain host cell components was greatly increased by incorporation into the makeup of the oncolytic virus. Footnotes Submitted: 8 March 1967

Miller, John J.; Cole, Leonard J.

doi: 10.1084/jem.126.1.109pmid: 6027642

The cells of the popliteal lymph nodes of rats were labeled for 4 days after a secondary immunological stimulus. 31 days after the last dose of tritiated thymidine, groups of rats were started on courses of daily, intraperitoneal injections of prednisone, cyclophosphamide, 6-mercaptopurine, or actinomycin D. The initially low doses of these agents were doubled in successive weeks until either lymphoid hypoplasia or death occurred. Rats from each group were killed weekly, and the percentages of persisting, labeled small lymphocytes in the popliteal nodes were determined. Sections of these nodes were examined for persisting, labeled plasma cells. The per cent of lymphocytes labeled increased while the total number of lymphocytes decreased during treatment with prednisone and cyclophosphamide. Prednisone decreased the numbers of long-lived plasma cells, but these cells were preferentially resistant to cyclophosphamide. Neither 6-mercaptopurine nor actinomycin D had an appreciable effect on lymphoid tissues histologically nor on the proportions of labeled, long-lived lymphocytes and plasma cells before causing the deaths of the rats receiving them. These results indicate that long-lived lymphocytes and plasma cells survive treatment with the immunolytic drugs studied, and that long-lived lymphocytes are specifically resistant to prednisone and cyclophosphamide. We believe these results have an application to the attempts to find drugs useful in the treatment of immunologic rejections of organ transplants, and for therapy of autoimmune diseases. Footnotes Submitted: 9 March 1967

Pearlman, David S.

doi: 10.1084/jem.126.1.127pmid: 6027643

The influence of antibody on antibody formation to particulate antigen was examined in the rabbit with special reference to the importance of immunoglobulin type, the amount and relative proportion of antigen and antibody involved, and the specificity of this influence. 19S as well as 7S antibody was shown to be an effective inhibitor of antibody formation, although there was some evidence that 7S antibody was the more efficient of the two in doing so. The inhibitory effect of antibody was found to be specific for homologous antigenic determinants. Both 19S and 7S antibody were also able to enhance antibody formation. In contrast to the suppressive phenomenon, however, enhancement appeared to be nonspecific since antibody reactive with homologous (sheep red blood cell) determinants could enhance the response not only to homologous determinants but to heterologous (dinitrobenzene) determinants conjugated to the red blood cells as well. Smaller amounts of antibody were needed to enhance than to suppress antibody formation, and suppression and enhancement depended to some extent on the amount of antigen as well as to the amount of antibody used. The enhancing and suppressing influence of antibody on antibody formation appeared to be exerted concomitantly, for the response to some antigenic determinants was sometimes suppressed at the same time that the response to others was enhanced. It is suggested that enhancement or suppression of immunologic responses by antibody represents a different balance of at least two competing factors operating together: specific neutralization of appropriate determinants thus decreasing the total effective concentration of these determinants available to stimulate the formation of antibodies, and a nonspecific increase in the availability of antigen to immunologically competent cells. Footnotes Submitted: 1 March 1967

Taylor, Fletcher B.; Ward, Peter A.

doi: 10.1084/jem.126.1.149pmid: 4226164

The addition of plasminogen and streptokinase to rabbit serum results in appearance of chemotactic activity which is relatively heat-labile and dialyzable. Generation of this activity requires heat-labile factors in serum, but not the sixth component of complement. The optimal mole ratio for generation of chemotactic activity is 1:1 to 1:3 for plasminogen to streptokinase. Neither material alone is sufficient to generate the activity in fresh serum. Generation of chemotactic activity can be blocked by the presence of ϵ-aminocaproic acid. This plasmin-generated chemotactic factor sediments slowly in a sucrose density gradient during ultracentrifugation. The addition of plasminogen and streptokinase to rabbit serum containing the preformed chemotactic factor (activated trimolecular complex of C'5, C'6, C'7) causes destruction of the chemotactic factor and loss of hemolytic activity of the sixth component of complement. The same mole ratio of reactants for optimal expression of the phenomenon holds as for plasmin generation of chemotactic activity in untreated serum. Footnotes Submitted: 5 February 1967