Studies of the immunological capacity of germ-free mouse radiation chimeras. II. Thymus cell function in a humoral immune response to sheep erythrocytes

Experiments described here were undertaken to determine the reason for the depressed humoral immune response in germ-free mouse allogeneic radiation chimeras. Indirect immunofluorescence using the theta (θ) antigen as a marker demonstrated that about 10% of the nucleated cells in the spleen of both allogeneic and syngeneic chimeras bear the θ antigen. One type of in vivo cell transfer assay employed to determine the capacity for “helper” function of thymocytes revealed that allogeneic chimera thymocytes were only 7–18% as efficient in “helper” function as normal thymocytes. A second type of in vivo cell transfer assay demonstrated that the presence of intact normal thymic stroma had no effect on the “helper” inefficiency of thymocytes obtained from allogeneic radiation chimeras.     

Studies of the immunological capacity of germ-free mouse radiation chimeras. IV. Cell-mediated immunity

The cell-mediated immune (CMI) response of germ-free mouse radiation chimeras was compared with that of conventional mice. Spleen or thymus cells from chimeric or normal mice were injected intravenously into lethally irradiated, allogeneic hosts. Spleens of the irradiated hosts were assayed for effector cells using the ⁵¹Cr release assay. Spleen cells from syngeneic and allogeneic chimeras and normal mice were equally active in giving rise to effector cells. However, thymus cells from allogeneic chimeras were completely inactive within 9 months post-bone marrow transplant while thymus cells from syngeneic chimeras and normal mice still remained functional. Although allogeneic chimeras contain cells potentially reactive toward host antigens, cells cytotoxic to host antigens were not detectable. In addition, these studies indicate the helper cell and effector cell, both associated with T-derived lymphocytes, represent two different populations.     

Studies of the immunological capacity of germfree mouse radiation chimeras. III. In vitro reconstitution of the T-helper cell deficiency

The plaque-forming cell (PFC) response of long-term radiation induced allogeneic bone marrow chimeric (ABMC) mice has been shown to be markedly deficient. The nature of the cellular deficiency of the primary PFC response was investigated using in vitro culture techniques. Adherent spleen cells from ABMC or DBA/2 mice support equally well the development of PFC from nonadherent DBA/2 spleen cells. Nonadherent cells prepared from ABMC mice when cocultivated with DBA/2 adherent cells showed a minimal response. However, the addition of activated DBA/2 T cells to cultures containing adherent cells from DBA/2 mice and nonadherent cells from ABMC mice completely reconstituted the in vitro response to sheep erythrocytes. Therefore a cellular deficiency of the humoral immune system of ABMC mice was shown to be associated with the thymus-derived lymphocyte pool.     

Gentic control of the immune response to the Ea-2 alloantigen system of the mouse. I. The humoral antibody response.

The immunization of selected congenic strains and hybrids against the Ea-2.1 cellular alloantigen of the mouse demonstrated that the hammagglutinating antibody response to Ea-2.1 is regulated by a gene or genes associated with the H-2 gene complex. H-2r and H-2b are, respectively, responder and non-responder haplotypes.     

Decreased cellular immune response of germ-free mice.

Cellular immune response to intracerebral lymphocytic choriomeningitis infection was studied in mice belonging to an identical strain but different in breeding conditions. In consequence of the cellular immune reaction on the leptomeninx, lymphocytic choriomeningitis developed and caused death in 100% of conventionally bred mice, whereas 80% of germ-free and 15% of mouse-pathogen-free mice failed to display lymphocytic infiltration of the leptomeninx and survived the infection as chronic virus carriers. This finding pointed to a deficient cellular immune response of germ-free and mouse-pathogen-free mice. The under-development of the lymphoid system due to the antigen-poor breeding conditions might be responsible for the deficiency.     

Ontogeny of the ferret humoral immune response.

Infant ferrets are born with nearly undetectable immunoglobulin levels, but by 9 days of age the infant ferret serum contains 77, 29, and 13% of adult mean serum levels of IgG, IgA, and IgM. Transmucosal uptake of IgG by the infant ferret occurred for the first 30 days of life. The specific anti-respiratory syncytial virus neutralizing titer of whole milk was 5.5 times higher than maternal serum despite a lower concentration of immunoglobulins in the milk.     

Transmission of hepatitis B to the rhesus monkey. Studies on the humoral and cell-mediated immune response.

The susceptibility of the rhesus monkey (Macaca mulatta) to hepatitis B virus was enhanced by the induction of chronic infection with Plasmodium inuei.     

Hepatitis delta antigen. Antigenic structure and humoral immune response

Hepatitis delta virus (HDV) is a small RNA virus that is dependent on helper functions provided by hepatitis B virus. The hepatitis delta Ag (HDAg) is the only protein known to be made from the viral genome, from an ORF with a coding capacity of 214 amino acids. The immunogenic epitopes of HDAg and the immune response to it were mapped by the use of synthetic peptides, antipeptide antibodies, and human mAb. Antipeptide sera covering approximately 60% of the linear sequence reacted with liver-derived HDAg. Antisera from HDV-infected humans, chimpanzees, and woodchucks reacted with from 2 to 13 of 15 peptides. The epitopes of two human anti-HD mAb were mapped to overlapping but distinct epitopes in the region around residues 106-123. Sera from infected humans, chimpanzees, and woodchucks were also tested by competition with the mAb. Use of the peptides and antipeptide sera defined one region in the sequence (residues 52-93) which is immunodominant in the immune response to HDAg. Reactivity of both peptides and antipeptide antibodies was very broad, covering most or all of the linear sequence. Competition assays also provided information on conformational epitopes, as well as the sequential epitopes defined by direct assays. The peptides and antipeptide antibodies should be useful in new assay development, in dissecting the anti-HD response in terms of chronic vs self-limited infection, and in studying the role of anti-HD in infection and recovery.     

Assessment of the humoral immune response to cancer

One of the deadly hallmarks of cancer is its ability to prosper within the constraints of the host immune system. Recent advances in immunoproteomics and high-throughput technologies have lead to profiling of the antibody repertoire in cancer patients. This in turn has lead to the identification of tumour associated antigens/autoantibodies. Autoantibodies are extremely attractive and promising biomarker entities, however there has been relatively little discussion on how to interpret the humoral immune response. It may be that autoantibody profiles hold the key to ultimately uncovering neoplastic associated pathways and through the process of immunosculpting the tumour may have yielded an immune response in the early stages of malignant tumour development. The aim of this review is to discuss the utility of the autoantibody response that is elicited as a result of malignancy and discuss the advantages and limitations of autoantibody profiling. This article is part of a Special Issue entitled: Translational Proteomics.     

Maturation of the humoral immune response as an optimization problem.

Efficient immune response often depends on the production of high affinity antibodies. We show analytically that the optimal strategy for a fast production of high affinity antibodies is to utilize a step-function mutation rate, i.e. a minimal mutation rate in early stages of the immune response, followed by a discontinuous switch to the maximal possible rate when the proliferating population of B-cells exceeds a threshold value. Our results are in accordance with the biological observations concerning the time of onset of the hypermutation process, and with the mutation rate during the later stages of the primary immune response. Indeed the hypermutation process plays a crucial role in responding to a prevailing pathogen at each round of immune response, and not only for coping with future infections. Moreover, as the effect of hypermutations is shown to be crucially dependent on the number of proliferating B-cells, its onset is not expected to depend on an external signal, but rather to be related to the clone's age. This suggests that the onset is host species specific, rather than pathogen specific. Another implication of the present results is that activation of hypermutations before the B-cell population has reached the critical size may impede the efficiency of the response.     

Effects of bile acids on the humoral immune response: a mechanistic approach.

Whereas bile acids in excess depress the cell-mediated immune response, their effects on the humoral response have been little investigated. The aim of this study was to investigate the effects of bile acids on immunoglobulin production. Human peripheral blood mononuclear cells were stimulated for 5 days by Staphylococcus aureus Cowan I (SAC-I). Immunoglobulins were measured in the supernatants and cell lysates using ELISA. We found that bile acids inhibited IgM production in a dose-dependent manner. The inhibitory effects of 50 microM chenodeoxycholic acid (CDCA) and its glyco- and tauro-conjugates (62, 53 and 51%, respectively) were stronger than those of ursodeoxycholic acid (UDCA) and its conjugates (45, 40 and 34%, respectively). The inhibition of IgG production by CDCA and UDCA was weak (23 and 12%, respectively, at 50 microM). IgA production was not modified. The inhibition of intracellular IgM concentration paralleled that observed in the secreted compartment. By contrast, CDCA enhanced intracellular concentration of IgG. In the absence of significant necrosis or apoptosis, CDCA-mediated inhibition of SAC-I-induced IgM production was significantly correlated to the ability of the bile acid to inhibit cell proliferation (r=0.98; p<0.05). In conclusion, we showed that hydrophobic bile acids strongly depress the primary humoral response. This effect resulted from both an inhibition of cell proliferation, and to a lesser extent from a deficient exocytosis of immunoglobulins.     

The cellular and humoral immune response to Schistosoma mansoni infections in inbred rats: I. Mechanisms during initial exposure

Fischer rats were infected with Schistosoma mansoni by exposure to cercariae. The effects of animal age at exposure and the size of that exposure were determined by quantitation of subsequent worm burdens. Optimal conditions for assay of protection mediated by cells or serum transferred from exposed donors were ascertained. The major initial protective immune response to infection was mediated by thymusdependent lymphocytes as demonstrated by discrete subpopulation cell transfer experiments. Simultaneously harvested serum enhanced worm survival and obviated the protective effects of transferred cells when serum and cells were given concomitantly. Subsquently, host immunity became dependent on antibody formation. In the chronic phase of infection, a small number of surviving parasites coexisted with antibody which specifically interacted with schistosomal antigens but did not protect in transfer experiments. These studies suggest a form of immunologic enhancement with antibody modulation of cellular immunity as possible components of the immune response to both acute and chronic schistosomiasis.     

Hymenolepis murissylvatici: humoral response in intestinal lavages of the mouse

Hymenolepis murissylvatici elicits a humoral response in serum and in the intestine of the mouse from which it is immunologically rejected. In serum, significant differences were recorded 3 days after reinfection, while in intestinal lavages it takes place from day 9 after reinfection. In serum the response is largely the result of IgG and IgM antibodies whereas in the intestine, IgA is the most abundant antibody. Although specific IgE could not be demonstrated in serum, it was present in intestinal lavages, although rather late (i.e. day 14 after reinfection). Treatment of young worms in vitro both with immune serum or intestinal lavages had no apparent effect on their viability. Immune serum produced a complement independent precipitation on the surface of the worms in vitro. This reaction did not affect viability or infectivity of the parasite, as demonstrated by the successful implantation of treated worms in recipient mice. The above-mentioned results, together with the knowledge that the Hymenolepis model has no tissue stages and causes no tissue damage, make it probable that further study of this model will reveal some specific intestinal immunological reactions.