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We studied humoral immunity to human thyroglobulin (hTg) during the course of multiple myeloma (MM). In this report, we describe the anti-hTg antibody activity in the sera of patients with MM. Among 63 sera tested, 28 (44%) had IgG anti-hTg autoantibodies (aAb), 16 (25%) exhibited IgM aAb, and six (9%) had IgA anti-hTg aAb. For the majority of sera the anti-hTg autoantibody activity was associated with more than one immunoglobulin class. IgG anti-hTg antibodies were observed in 9/11 patients with IgA MM and in 19/40 patients with IgG MM. The IgM anti-hTG antibody activity was found in the sera of 11 patients with IgG MM. These results show that the anti-hTg activity in these patients is associated with residual polyclonal immunoglobulins. However, in the serum of one patient presenting a double monoclonal gammopathy (IgG and IgA lambda MM), the anti-hTg activity was carried by both the IgG lambda and the IgA lambda molecules, suggesting that in this case the activity was due to the monoclonal immunoglobulin itself. We also studied the epitopic specificity pattern of all these anti-hTg aAb. Only three sera recognized one antigenic region on hTg, suggesting that the majority of the anti-hTg aAb in MM patients were directed against antigenic regions other than those recognized by our panel of murine mAb. In conclusion, our results demonstrated that humoral immunity to hTg is maintained in MM patients. These data contrast with the well-documented suppression of immunity to foreign, especially bacterial, antigens described in MM.
The widely expressed tumour antigens hTERT and CYP1B1 are commonly expressed in multiple myeloma (MM) cells. Several trials targeting these antigens by immunotherapy have been initiated. The aim of this study was to explore whether patients with MM have an endogenous pre-existing immune response against recently identified epitopes from hTERT and CYP1B1. Peripheral blood T cells from 27 HLA-A*0201+ multiple myeloma patients at different stages of disease and 20 healthy HLA-A*0201+ donors were enriched and studied for the presence of hTERT- and CYP1B1-specific cytotoxic T cells using MHC tetramer detection and short-term ex vivo expansion. No significant expansion of tetramer-positive cells was detected in the peripheral blood of either MM patients or healthy controls when cells were stained with tetramers containing the dominant hTERT-derived epitope or two peptides derived from CYP1B1. A single ex vivo peptide stimulation led to the detection of a small population (0.3-0.5%) of hTERT-specific cells in two of 27 patients with MM. None of the patients or controls showed significant expansion of CYP1B1-specific cells after a single peptide stimulation. Thus, endogenous in vivo priming of T cells against hTERT and CYP1B1 is a rare event in MM patients. These results suggest that strategies targeting hTERT and CYP1B1 may have to utilize techniques to induce T cell responses from a naive precursor frequency.
Protective immunity against a lethal, Y strain, T. cruzi infection could be transferred to normal mice by either serum or spleen cells from mice which had recovered from the acute phase of infection. The ability of spleen cells to transfer immunity was abolished by B lymphocyte removal (anti-Ig column fractionation), but was relatively insensitive to T lymphocyte depletion (anti-Thy 1.2 plus complement) or macrophage removal (Sephadex G-10 fractionation). Immune spleen cells gave an anamnestic antibody response when injected together with T. cruzi antigen into lethally irradiated recipients and these antibodies conferred protection in a passive transfer system. T cell depletion reduced, but did not abolish, this antibody response. These data imply that the protective immunity of T. cruzi-convalescent mice is predominantly B cell-mediated with T cell involvement being restricted to a helper role.
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HLA D locus-related (DR) antigens and Gm phenotypes were determined in 30 patients with epidemic polyarthritis following Ross River virus (RRV) infection and contrasted with those in comparison series of 119 (DR) and 1220 (Gm) normal subjects. HLA DR7 (46.7% cf. 21.0%) and the heterozygous Gm phenotype a+x+b+ (33.3% cf. 15.3%) were significantly increased in the patients, with relative risks of 3.3 and 2.8 respectively. The occurrence of Gm a+x+b+ was independent of DR7, and conferred a relative risk of 4.3 in DR7-negative patients. Differences found in clinical features, specific lymphocyte proliferative responses and antibody titres did not reach significant levels. The association with DR7 was inversely related to age in residents of an area of moderate endemic risk, and to levels of natural cell-mediated immunity (natural killer cell activity). These correlations point to possible mechanisms by which genetic traits might influence the occurrence or consequence of RRV infection.
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The promastigote surface antigen-2 (PSA-2) is a Leishmania parasite antigen, which can induce Th1-mediated protection against murine leishmaniasis when used as a vaccine. To evaluate PSA-2 as a human vaccine candidate the specific T-cell response to PSA-2 was characterised in individuals immune to cutaneous leishmaniasis. Peripheral blood mononuclear cells from Sudanese individuals with a past history of self-healing cutaneous leishmaniasis proliferated vigorously in response to PSA-2 isolated from Leishmania major, whereas the antigen did not activate cells from presumably unexposed Danes. Peripheral blood mononuclear cells from individuals with previous L. major infection had varying proliferative responses to PSA-2 derived from L. donovani promastigotes. Peripheral blood mononuclear cells activated by PSA-2 from L. major produced high amounts of interferon-gamma and tumour necrosis factor-beta, and little interleukin-4, thereby showing a Th1 cytokine pattern. Parallel cultures showed clear Th1 and Th2 response patterns to purified protein derivative of tuberculin or tetanus toxoid, respectively. Flow cytometric analysis revealed that PSA-2 induced blastogenesis in the CD3 positive population and that these cells were the major source of interferon-gamma. The results show that Th1-like cells recognising PSA-2 are expanded during infection by L. major and that they maintain their Th1-like cytokine profile upon reactivation in vitro. Since immunity to cutaneous leishmaniasis is mediated by antigen-specific Th1-like cells, PSA-2 might be considered a vaccine candidate for human leishmaniasis.
The ability of naturally infected and cured mice to resist reinfection with tick-transmitted Borrelia burgdorferi was tested over a 1-year period. All of the mice were resistant to reinfection when they were challenged at 1.5 months after cure. The majority of animals were resistant to reinfection for up to 10.5 months after cure, but this resistance was lost at 1 year after cure. Both protected and unprotected animals showed a diverse array of antibodies on Western immunoblots. Protection was not associated with the killing of spirochetes in ticks, and naturally infected mice produced no antibodies to outer surface protein A (OSP A). The titers to whole Borrelia sonicate and OSP C, however, remained high throughout the 1-year study period. The levels of borreliacidal antibodies were highest in the 1.5 month-after-cure group. Natural immunity to reinfection with B. burgdorferi is limited in time, is complex, and may involve both humoral and cellular components.
Why there are so few gametocytes (the transmission stage of malaria) in the blood of humans infected with Plasmodium spp. is intriguing. This may be due either to reproductive restraint by the parasite or to unidentified gametocyte-specific immune-mediated clearance mechanisms. We propose another mechanism, a cross-stage immunity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1). This molecule is expressed on the surface of the erythrocyte infected with either trophozoite or early gametocyte parasites. Immunoglobulin G antibodies to PfEMP-1, expressed on both life cycle stages, were measured in residents from an area where malaria is endemic, Papua New Guinea. Anti-PfEMP-1 prevalence increased with age, mirroring the decline in both the prevalence and the density of asexual and transmission stages in erythrocytes. These data led us to propose that immunity to PfEMP-1 may influence malaria transmission by regulation of the production of gametocytes. This regulation may be achieved in two ways: (i) by controlling asexual proliferation and density and (ii) by affecting gametocyte maturation.
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The autoimmune repertoire is well known from previous studies to be capable of producing catalytic antibodies directed to self-antigens. In the present study, we explored the ability of 26 monoclonal light chains (L chains) from multiple myeloma patients to cleave radiolabeled gp120, a foreign protein. One L chain with this activity was identified. 125I-gp120 and unlabeled gp120 were cleaved at several sites by the L chain, as shown by SDS-polyacrylamide gel electrophoresis, autoradiography, and immunoblotting, respectively. The apparent dissociation constant of the L chain was 130-145 nM, indicating high-affinity gp120 recognition. 125I-albumin was not cleaved by the L chain, and various proteins and peptides did not inhibit gp120 cleavage by the L chain, suggesting that the activity is not a nonspecific phenomenon. The substrate recognition determinants may be conserved in different HIV-1 strains, because gp120 isolated from strains SF2, MN, and IIIB was found to be cleaved by the L chain. Micromolar concentrations of a synthetic peptide corresponding to residues 23-30 of gp120 inhibited the cleavage of 125I-gp120, suggesting that these residues are components of the epitope recognized by the L chain. The toxic effect of gp120 in neuronal cultures was reduced by about 100-fold by pretreatment of the protein with the L chain. These observations open the possibility of utilizing gp120-cleaving antibodies in the treatment of AIDS.
There is extensive evidence that changes in immune system activation accompany the pathological changes of Alzheimer's disease (AD), but a mechanistic understanding of how the immune system actually participates in disease pathogenesis is still largely lacking. Because of the complexity of the immunological response, and the difficulty in identifying the key molecular players that underlie any given immunological response, expanding our understanding of the immunological response in AD beyond its descriptive stages has not been a straightforward exercise. The development of transgenic animals that form deposits of Abeta peptide in their brains has provided an unexpected dividend to those interested in the immunological response characterizing AD. Several of these transgenic models develop structures greatly resembling neuritic plaques, a hallmark feature of AD brain that is also a focal point of the immunological response occurring in AD. Genetic and pharmacological manipulation of these Abeta-depositing transgenic mice is providing some intriguing and unexpected insights into the role of innate and adaptive immune mechanisms in the pathogenesis of AD. This review will discuss immunological perspectives that have arisen from research using Abeta-depositing transgenic mice, and place these perspectives in the context of epidemiological and genetic studies that have previously suggested a role for the immune system in AD. The emerging story affirms the likely role of innate and adaptive immune mechanisms in the pathogenesis of AD, but provides a cautionary note as to the difficulties that are likely to face potential immunomodulatory therapies due to the dualistic beneficial and detrimental roles that immune mechanisms appear to play in AD.
This article will introduce a novel concept in the use of TGF-beta insensitive host immune cells in cancer therapy. TGF-beta is a multi-functional cytokine. At a cellular level, it mediates cellular proliferation, growth arrest, differentiation and apoptosis. Because of the above cellular effects, TGF-beta is able to regulate a host of patho-physiological events in vivo, such as normal embryonic development, angiogenesis in tumor tissues, malignant transformation and immune surveillance. As a general rule, its direct effect on cancer cells is inhibition to cancer growth. However cancer cells are able to acquire the ability to evade this inhibitory effect of TGF-beta by becoming insensitive to TGF-beta. Furthermore, these malignant cells are able to produce large quantities of TGF-beta. The consequence of over expression of TGF-beta by cancer cells is an important factor for subsequent tumor progression. The excess amount of TGF-beta promotes tumor angiogenesis and immune suppression. The latter effect of TGF-beta is the most devastating to the host. The present discussion is focused on the role of TGF-beta insensitive immune cells in cancer growth. The host immune system offers a natural defense program against cancer. But, this natural immune surveillance is rendered ineffective by an overproduction of TGF-beta derived from the tumor cells. Rendering the host immune cells insensitive to TGF-beta in a gene therapy program offers a hope for us to successfully combat against cancer. Based on the above discussion, it is encouraging that there is a possibility for us to achieve a cure in cancer using TGF-beta insensitive immune cells in gene therapy.