Natural Thymocytotoxic Autoantibody Research Articles

Natural thymocytotoxic autoantibodies in non-obese diabetic (NOD) mice: characterization and fine specificity

The NOD mouse is a model of human juvenile type I diabetes mellitus. As in humans and in the BB rat model, the development of diabetes in NOD mice is accompanied by evident manifestations of cell-mediated and humoral autoimmunity. Beside autoantibodies directed at putative islet cell antigens, NOD sera contain antibodies with specificity for lymphocyte cell-surface determinants. Here we demonstrate that these anti-lymphocyte antibodies have the same characteristics of target cell specificity, of isotype, and of temperature reactivity, as do natural thymocytotoxic autoantibodies (NTA) from lupic NZB mice, or from mice undergoing polyclonal B cell activation. We also demonstrate that the thymocytotoxic activity of NOD sera is not due to cross-reactive anti-insulin antibodies. Biochemical characterization of the determinants recognized by these anti-lymphocyte antibodies reveals two membrane-associated proteins of 28 and 33 kD, partially similar to the two peptides recognized by NTA from NZB mice (30 and 33 kD). Altogether, these results suggest that NOD mice develop manifestations of polyclonal B cell activation similar to those observed in lupus-prone mice. The relationship of these anomalies with the organ-specific pancreatic disease remains to be properly evaluated.

Decreased acetylcholine content and choline acetyltransferase mRNA expression in circulating mononuclear leukocytes and lymphoid organs of the spontaneously hypertensive rat

It has been confirmed that the neurotransmitter acetylcholine (ACh) is present in blood; it is synthesized in T-lymphocytes by choline acetyltransferase (ChAT) and released upon T-lymphocyte activation. Both muscarinic and nicotinic ACh receptors have been identified on lymphocytes isolated from thymus, lymph node, spleen and blood, and their stimulation by muscarinic and nicotinic agonists elicits a variety of functional and biochemical effects, providing a strong argument that ACh synthesized and released from T-lymphocytes acts as an autocrine and/or paracrine factor regulating immune function. In the present study, we compared ACh levels in the blood, circulating mononuclear leukocytes (MNLs), thymus and spleen of spontaneously hypertensive rats (SHRs), which exhibit immune deficiencies related to the emergence of natural thymocytotoxic autoantibody, age-related decline of T-cell function and morphological changes in immune organs, with ACh levels in age-matched, normotensive Wistar Kyoto rats. In each case, ACh levels in 5-, 10- and 20-week-old SHRs were significantly lower than in WKYs. ChAT mRNA expression in MNLs was also significantly depressed in the SHRs. These results suggest that diminished synthesis and release of ACh from MNLs into blood and lymphoid organs likely reflects an immune deficiency related to T-cell dysfunction.

Vitamin E prevents the decrease of cellular immune function with aging in spontaneously hypertensive rats

This study was performed to investigate the mechanism of vitamin E (VE) induced restoration of cellular immune functions decreased with aging in spontaneously hypertensive rats (SHR). Both Wistar Kyoto rats (WKY) as control rats and SHR, 3 weeks old, were fed a diet supplemented with 50 or 585 mg VE/kg diet for 37 weeks. The changes in proportions of thymocyte subsets with aging were not significantly different between WKY and SHR. On the contrary, the expressions of both CD4 and CD8 antigens in CD4 +CD8 + thymocytes were significantly reduced in SHR compared to those of WKY at the same age, which was significantly improved by taking the high VE diet at 6 or 12 weeks old. Furthermore, the production of interleukin 2 (IL2) from thymocytes was also decreased in SHR compared to WKY, which was improved by both high VE diet and in vitro treatment with indomethacin, inhibitor of PGE 2 synthesis. In addition, natural thymocytotoxic autoantibody (NTA) titer in serum of SHR was also increased with aging and this increase was suppressed by feeding high VE diet until 12 weeks old after which it showed the same trend as that of SHR fed the control diet. These results suggest that VE induces the prevention in cellular immune functions decreased with aging in SHR, which is due to the increased production of IL2 and the decreased production of NTA from thymocytes following VE supplementation.

Functional CD4+ T cell subsets defined by expression of CD45RC and NTA260 antigens and age-associated polarization in murine lupus.

Using two mAb, one specific to the alternative exon 6-dependent epitope of CD45 molecules (JH6.2) and one a natural thymocytotoxic autoantibody (NTA) with an unknown reactive epitope (NTA260), we subdivided splenic CD4+ T cells from 2-month-old BALB/c mice into five phenotypically distinct subsets. CD45RC+NTA260- (S I) cells were phenotypically analogous to CD4+ T cells predominating in newborn mice and produced a significant amount of IL-2, but not so IL-4, IL-10 or IFN-gamma when stimulated with immobilized anti-CD3 mAb in vitro. They appeared to consist mainly of naive ThP cells. The CD45RC+NTA260+ (S II) subset also produced IL-2, but not other cytokines; however, the IL-2 levels produced were much higher than seen with the S I subset, thereby suggesting the predominance of further maturated ThP cells. The CD45RC-NTA260+ (S III) subset mainly produced IL-4, IL-10, IFN-gamma and less IL-2, and contained memory cells that helped the secondary antibody response to a recall antigen, and hence contained Th2 and probably a mixture of Th0 and Th1 cells. The CD45RC-NTA260- (S IV) subset was a poor responder to the immobilized anti-CD3 mAb. The CD45RCbrightNTA260dull (S V) subset consisted of a small number of cells that were phenotypically analogous to activated CD4+ T cells. While an age-associated decrease in the proportion of S I and less markedly in S II and in turn increase in S III subsets of CD4+ T cells occurred in normal BALB/c mice, autoimmune disease-prone (NZB x NZW)F1 mice showed a marked age-associated decrease in the proportion of not only S I, II but also III subsets. As aged (NZB x NZW)F1 mice carry CD4+ T helper cells for IgG anti-DNA antibody production, such age-associated polarization to the S IV subset appears to be critical in the pathogenesis of autoimmune disease in these mice.

Spontaneous development of anti-collagen type II antibodies with NTA, and anti-DNA antibodies in senescence-accelerated mice.

We previously reported that circulating natural thymocytotoxic autoantibody (NTA) and IgG-anti-DNA antibodies were the major serological characteristics of a substrain of SAM, SAM-P/1. We present here a study of ageing in which we further measured and compared various kinds of circulating IgG antibodies including anti-collagen type II, rheumatoid factor (RF), and anti-2,4,-dinitrophenol (DNP), between SAM-P/1 and control SAM-R/1 mice. The results showed that age-associated increases in anti-collagen type II antibodies in SAM-P/1 were distinctively higher than those in SAM-R/1 when the mice were over 4 months of age, and the increases were significantly correlated with increases in NTA, anti-DNA antibodies, RF activities and anti-DNP antibodies. Anti-collagen type II antibody activity was not significantly inhibited by preincubating the antibodies with DNA, IgG-Fc and DNP-BSA samples. These findings suggest that antibodies specifically directed against collagen type II can be produced in a background of polyclonal B cell activation, and that these antibodies in association with NTA and anti-DNA antibodies may play a pathogenic role in the development of accelerated senescence in SAM-P/1 mice.

A thymocytotoxic autoantibody reacts with the mouse brain cells in culture

Autoimmune-prone New Zealand Black mice produce a large amount of autoantibodies cytotoxic for thymocytes (natural thymocytotoxic autoantibodies, NTA). A monoclonal NTA (NTA260) has been found to react with brain tissues as well as the cell surface of thymocytes. We investigated the expression of NTA 260 antigen in the primary culture of fetal brain cells. NTA260 labeled strongly the cytoplasm of nerve cells after fixation, but failed to stain the living cells. Western blot analysis revealed that NTA260 recognized predominantly a band at approximately 53 kDa in brain and thymic extracts. These findings indicate that neuronal NTA260 antigen, which has a molecular mass similar to that of thymocytes, is likely an intracellular component.

An early activation antigen of murine T cells recognized by monoclonal natural autoantibody NTA204 and the expression on T cells from aged NZB x NZW F1 mice with overt autoimmune disease.

A monoclonal natural thymocytotoxic autoantibody NTA204 established from an autoimmune-prone NZB mouse reacted with the majority of thymocytes, all peripheral B cells, granulocytes and bone marrow myeloid cells, but not with peripheral resting T cells of normal mice. In aged NZB/W F1 mice with overt autoimmune disease, the population of NTA204+ CD4+ CD25- T cells was remarkably increased. The NTA204 antigen could be induced on splenic T cells from normal healthy mice as early as 3 hr after the initiation of culture with stimulant Con A, and was expressed on the vast majority in the 48-hr culture. The expression preceded that of other T cell activation antigens tested, CD25 and CD45R. Cell cycle analysis suggested that NTA204 is expressed at an early phase of G1A. T cells, particularly CD8+ T cells, in the allogeneic mixed lymphocyte culture (MLC) could be divided into two populations, NTA204+ and NTA204-. By immunohistochemical analysis, 30% of NTA204+ CD8+, but few NT204- CD8+ T cells were intensely positive for large cytoplasmic granules of perforin, an important cytolytic mediator of cytotoxic T cells. Thus the increased population of NTA204+ T cells in aged NZB/W F1 mice appear to be activated T cells and might be at least partly involved in the pathogenesis of disease in these mice. Immunoblotting analysis of Con A-activated splenic T cells showed that NTA204 molecules have a molecular mass of 49 Kd.

Two distinct monoclonal natural thymocytotoxic autoantibodies from New Zealand black mouse

Autoimmune-prone NZB and NZB × NZW F1 mice have a large amount of autoantibodies cytotoxic for thymocytes (natural thymocytotoxic autoantibodies, NTA). We established two distinct monoclonal NTAs (NTA260 and NTA204) from a NZB mouse that react with the majority, but not all of these thymocytes. Flow cytometry analysis showed that NTA260 is positive on subpopulations of peripheral T cells from young mice, in which approximately 65% of CD4 + and 85% of CD8 + T cells were NTA260 +. NTA260 also reacted with brain tissues of mice and rats, including Purkinje cells in the cerebellum. Western blot analysis showed that the molecular weight of NTA260 antigen was 55 kDa. In contrast to NTA260, NTA204 reated with peripheral B cells but not with peripheral T cells in mice. NTA204 also reacted with peripheral blood granulocytes and bone marrow myeloid cells from both mice and rats. An immunofluorescence inhibition assay revealed the presence of autoantibodies with specificities of each NTA260 and NTA204 in the sera from NZB mice. As a selective decline in the subset of NTA260 + T cells but not NTA204 + B cells was observed with aging of NZB and NZB × NZW F1 hybrid mice, NTA260 is at least partly related to the observed immunological abnormalities of T cells in these autoimmune-prone New Zealand mice.

In vitro functional characterization of SAG-3--a naturally occurring monoclonal antibody in NZB mice: specificity toward functional T cell subsets.

Natural thymocytotoxic autoantibodies (NTA) have been suggested to contribute to the T cell mediated immune dysfunction prevalent in NZB mice. However, direct studies to confirm these suggestions have been difficult to perform due to the absence of large amounts of pure NTA. To overcome this problem, we generated a naturally occurring monoclonal antibody from an NZB mouse which possesses the serological characteristics of serum-NTA. Herein, we report the in vitro functional characteristics of this monoclonal antibody designated SAG-3. In vitro treatment of spleen and lymph node cells from BALB/c mice with SAG-3 and complement eliminated most of the proliferative response to Con-A and moderately reduced the response of these cells to PHA-P and PWM. Complement mediated cytolysis of SAG-3 reactive cells significantly reduced the capacity of unprimed lymph node cells to generate primary CTL responses in vitro against allogeneic cells. However, only a partial decrease in CTL activity was observed when primed secondary CTL effector cells were treated, due primarily to the depletion of CTL's specific towards MHC class I antigens. Furthermore, a moderate reduction in antigen-specific helper T cell function was observed. Pretreatment of responder cells with SAG-3 + C' did not appear to reduce the proliferative MLR response to a wide range of stimulator cells. In addition, contrary to previous reports on serum-NTA, SAG-3 appears not to be reactive against Con-A induced suppressor T cells. Finally, by FACS analysis SAG-3+ thymocytes constitute an overlapping population of Lyt-2+ and L3T4+ thymocytes. These findings are discussed in comparison to previous reports on NTA.

Depression of T cell-mediated immunity and enhancement of autoantibody production by natural infection with microorganisms in spontaneously hypertensive rats (SHR).

We studied the effects of breeding conditions on the development of immunological abnormalities in spontaneously hypertensive rats (SHR) with congenital T cell depression. The depression of T cell functions, the production of natural thymocytotoxic autoantibody (NTA), and the development of polyarteritis nodosa were more evident in SHR reared under a conventional (CV) environment than in specific-pathogen-free (SPF) SHR bred in a semi-barrier system. Enhancement of these immunologic abnormalities was also observed by the conventionalization of SPF-SHR. A high frequency of antibodies to mouse hepatitis virus (MHV), Sendai virus, and Mycoplasma pulmonis was detected in CV rat sera, whereas no antibodies were detected in SPF-SHR. The experimental infection of Sendai virus induced the enhancement of T cell depression and of NTA production in SPF-SHR. We interpret these results to mean that the natural infection of microorganisms causes an acceleration of immunologic abnormalities in SHR reared in a CV environment.

Characterization of two molecules at 30,33 kDa as major target antigens of natural thymocytotoxic autoantibodies

We have attempted to characterize, by immunoblotting, the cell surface determinants which are recognized by natural thymocytotoxic autoantibodies (NTA). NTA-positive sera from spontaneously autoimmune mice and from mice rendered autoreactive by neonatal induction of tolerance were used as probes on blots of thymocytes. Fifty percent of the sera screened under these conditions reacted with a doublet of 30,33 kDa molecular weight present on membranes, but not detectable on blots of total cell extracts. Additional bands of various molecular weights were detected by NTA-positive sera at a much lower frequency than the 30,33 kDa determinants. Direct evidence of identity between the antibodies inducing thymocytotoxicity and those detecting the doublet in immunoblotting was provided by immunoadsorption tests. Among a panel of immunoadsorbents prepared with thymocyte membrane proteins of various molecular weights, only the one containing the 30,33 kDa molecules efficiently adsorbed cytotoxic antibodies whereas the other preparations containing some of the bands occasionally detected in immunoblotting had practically no effect. In addition we showed that the 30,33 kDa doublet is also detected on membrane preparations of T and B lymphocytes but not on preparations of a non-lymphoid cell line, and is composed of two independent molecules not covalently linked, in their native configuration, by disulfide bonds. Altogether these results strongly suggest that the 30,33 kDa molecules represent major cell surface determinants for thymocytotoxic autoantibodies.

The effects of pepsin on the natural progression of autoimmunity in glomerulonephritis in the NZB/W F 1 mouse

The effects of pepsin on autoimmune glomerulonephritis of New Zealand Black and White F 1 hybrid (NZB/W F 1) mice were investigated. Intravenous pepsin significantly improved survival rate and suppressed progressive increase in urinary protein and histopathological changes in kidney. Increased serum levels of immune complexes, anti-DNA antibody and natural thymocytotoxic autoantibody were decreased and abnormalities in lymphocyte subsets were ameliorated by pepsin. Pepsin suppressed autoantibody production and enhanced antibody production against xenogeneic substance in these mice. The fact that pepsin ameliorates abnormalities in immune function may contribute to the preventive effects of pepsin against pathogenesis and progression of immune complex nephritis.

Enhancing effect of H-2-linked NZW gene(s) on the autoimmune traits of (NZB X NZW)F1 mice.

To investigate the possible enhancing effect of the H-2z haplotype of the New Zealand White (NZW) strain on the production of autoantibodies and renal disease observed in B/W F1 mice, we developed the ZWD/8 strain, a NZW congenic line carrying the H-2d haplotype, produced (NZB X ZWD/8)F1 (B/WD8 F1) mice, and examined the difference in several immunological abnormalities between the B/W F1 (H-2d/H-2z) and the B/WD8 F1 (H-2d/H-2d) mice. In comparison with B/W F1 mice, the B/WD8 F1 mice showed markedly lower serum levels of the anti-DNA antibodies and the gp70 ICs, and a later onset and a lower incidence of proteinuria with a lower mortality. In contrast, there was no significant difference in the incidences and the amounts of both natural thymocytotoxic autoantibody and anti-erythrocyte autoantibody between these two hybrid strains. Further, the serum levels of IgG and IgM in B/WD8 F1 mice were as high as those in B/W F1 mice. These findings indicate that the gene(s) that is within or closely linked to the H-2 complex of NZW strain specifically acts to intensify the levels of anti-DNA antibodies and gp70 ICs, and to promote the severity of renal disease in B/W F1 mice. This gene may play a role in the class conversion of anti-dsDNA antibodies from IgM to IgG.

Genetic regulation of erythrocyte autoantibody production in New Zealand black mice.

The incidences of positive anti-erythrocyte autoantibodies (AEA) in New Zealand Black (NZB), C57BL/6, their F1, F2 hybrid, and the F1 X NZB backcross mice were 100, 0, 0, 17, and 51%, respectively. This finding is in keeping with the idea that a combined effect of one to three dominant predisposing NZB gene(s) and a single dominant modifying C57BL/6 gene regulates the AEA production. Studies suggested that the modifying locus Aem-1 is loosely linked to Mup-1 locus on chromosome 4, and the gene order is Aem-1: Mup-1: Gpd-1. We analyzed the effects of the Aem-1 locus on other autoimmune traits and found that the gene action of Aem-1 is unrelated to the spontaneous productions of dsDNA-specific antibodies, the retroviral gp70-anti-gp70 immune complexes and natural thymocytotoxic autoantibodies and to the serum level of retroviral gp70. A significant association was observed between the negative AEA and the low (normal) serum IgM level in (C57BL/6 X NZB)F1 X NZB backcross mice. It remains to be determined whether the Aem-1 locus also controls the serum IgM level.

Subpopulation of T cells sensitive to natural thymocytotoxic autoantibody (NTA) of New Zealand mice. I. Distinct cytotoxic sensitivity of functional T cell subsets to NTA and anti-thy-1 antibodies.

NZB mice produce a natural thymocytotoxic autoantibody (NTA) capable of specifically injuring thymocytes and T cells. NTA-reactive antigen (NTA-A) shows a different density distribution among T cells, and partial killing with NTA and complement can eliminate T cells bearing NTA-A in high density. Thy-1 antigen is similar to NTA-A in this respect. To determine the effects of NTA and anti-Thy-1 on distinct functional subsets of T cells, Con A-induced suppressor T cell (Con A-Ts) activity against the allogeneic mixed lymphocyte reaction (MLR), responding T cell (TMLR) activity in the allogeneic MLR, and Con A-induced cytotoxic T cell (Con A-Tc) activity were examined simultaneously in BALB/c spleen cells before and after partial elimination of NTA- and anti-Thy-1-sensitive T cells. Treatment with NTA and complement resulted in a marked reduction in Con A-Ts activity, a significant increase in TMLR-activity and a slight and inconstant decrease in Con A-Tc activity. Since Con A-generated T's were much less sensitive to NTA, the NTA-sensitive T cells involved in Con A-Ts activity appear to be precursors or promoters of the Con A-Ts. In contrast, the precursors of Con A-Tc seem to relatively resistant to NTA. The increase in TMLR activity caused by NTA suggests the possibility that NTA is less cytotoxic for TMLR and cytotoxic for some suppressor T cells in allogeneic MLR. The monoclonal anti-Thy-1 antibody showed no such preferential cytotoxic effects on the three T cell functions. The NTA-sensitive T cells, in contrast to anti-Thy-1-sensitive T cells, were reduced gradually during Con A stimulation. All these findings indicate that NTA-A not only differs from Thy-1 antigen but that it appears to be a unique T cell antigen.

Induction of autoimmune phenomena in normal mice treated with natural thymocytotoxic autoantibody.

Natural thymocytotoxic autoantibody (NTA) developed spontaneously in New Zealand Black (NZB) mice consists of two autoantibodies in terms of target cell specificity. One of the autoantibodies, NTA-2, is strongly cytotoxic only against desialized lymphocytes, whereas the other one, NTA-1, is cytotoxic against both intact thymocytes and asialolymphocytes. To study the pathogenic role of NTA in murine autoimmunity, DBA/2 mice were injected every other day with affinity-purified NTA (NTA-1, NTA-2). Control mice received normal mice sera (NMS) or saline. After 20 days of treatment, spleen cells from DBA/2 mice treated with NTA-1 or NTA-2 showed a significant increase in the number of anti-ssDNA plaque-forming cells and IgM-producing cells. Sera from NTA-treated mice showed greater DNA binding than sera from control mice did. The levels of proteinuria were moderately increased in NTA-2-treated mice. Con A responsiveness of thymocytes was markedly reduced in NTA-2-treated mice. On the other hand, Con A-activated spleen cells from both control and NTA-treated mice equally suppressed anti-SRBC antibody production in vitro, suggesting that NTA treatment didn't affect the direct precursors of suppressor T cells. Finally, prior absorption of NTA-1 by thymocytes prevented its ability to induce anti-DNA antibodies; however, prior absorption of NTA-2 by thymocytes didn't affect its activity.

Restoration of T cell depression and suppression of blood pressure in spontaneously hypertensive rats (SHR) by thymus grafts or thymus extracts.

Spontaneously hypertensive rats (SHR) that develop hypertension and arterial lesions resembling human periarteritis nodosa were found to possess a selective depression of T cell functions with an appearance of natural thymocytotoxic autoantibody (NTA). The relationship between T cell depression and hypertension in these animals was investigated. The immune responsiveness of T cell-depressed SHR was completely recovered by histocompatible thymus grafts and was partially restored by histoincompatible allogeneic or xenogeneic thymus grafts or by injection of thymus extracts. Transplantation of compatible thymus tissues into neonatal SHR produced long-lasting recovery of immune functions. When complete immunologic restoration was achieved, significant suppression of high blood pressure was obtained. The SHR that showed high blood pressure were always accompanied with high NTA titers and arterial lesions. Thymus grafts or thymus extracts significantly decreased the titers of NTA. The development and dissemination of arterial lesions, which may cause increased blood flow resistance, were completely prevented by compatible thymus grafts into neonatal SHR. These results suggest that thymus grafts and thymus extracts may suppress the development of hypertension by preventing or curing the periarteritis nodosa in SHR.

Dietary fat affects immune response, production of antiviral factors, and immune complex disease in NZB/NZW mice.

Autoimmune-prone (NZB x NZW)F1 (B/W) mice fed three nearly isocaloric diets with varied fat content showed a marked difference in their spontaneous development of immune complex disease and their immune response. Those animals received the diets high in either unsaturated or saturated fats had more severe immune complex nephritis and died earlier than mice on the low-fat diet. Endogenous production of the mouse xenotropic virus was unaffected by dietary fats, but the serum lipoproteins associated with antiviral activity were increased to levels as high as 1:600,000 in the B/W mice on the high-fat diets. These lipoproteins may be partially responsible for the decreased mitogenic response of spleen cells from mice fed the two high-fat diets. The mice receiving a diet high in saturated fats produced substantially higher titers of natural thymocytotoxic autoantibody, an IgM class of antibody, than did the mice maintained either on the high-unsaturated-fat or low-fat diet. In contrast, the mice receiving the diet high in unsaturated fats made significantly greater levels of antibodies to double-stranded DNA, an IgG, than did the mice kept on the two other diets. These results suggest that the type of fat in the diet could affect the serum level of different immunoglobulin classes. The data provide further evidence that the amount of dietary lipids alone can influence cellular and humoral immune responses and the spontaneous development of immune complex disease.

Natural cytotoxic autoantibody against thymocytes in spontaneously hypertensive rats

A strain of SHR rats, which spontaneously develops hypertension and periarteritis nodosa, had a decreasing number of rosette-forming T cells in their thymuses and a progressive decline in cellular immune functions by aging. They were found to produce natural thymocytotoxic autoantibody (NTA) detected by a complement-dependent cytotoxicity test. This autoantibody occurred from 1 month of age and throughout life; the incidence was more than 60% of SHR rats at any age. Thymocytes from all six rat strains tested showed similarly high sensitivity to NTA but none of the strains tested produced NTA except the SHR strain. Rosette-forming thymocytes of WKA rats, which were separated by Ficoll gradient, showed much higher cytotoxic sensitivity to NTA than did whole thymocytes and nonrosetting thymocytes. The cytotoxicity of NTA was weak or negative for spleen cells, lymph node cells, bone marrow cells, and blood lymphocytes of WKA rats. However, the cytotoxic activity of NTA was completely absorbed with the thymus, spleen, lymph node cells, and brain homogenates and was partially absorbed with bone marrow cells, but not with liver and kidney homogenates. NTA in SHR rats was an IgM-globulin as determined by sensitivity to 2-ME treatment and by Sephadex G-200 column chromatography. These results suggest that NTA is responsible for the selective suppression of T-cell functions in SHR rats.

Natural Cytotoxic Autoantibody Against Thymocytes in Spontaneously Hyper tensive Rats

Spontaneous hypertensive rats produced a natural thymocytotoxic autoantibody (NTA) which was cytotoxic for the thymocytes of the various strains of rats tested. More than a 60% incidence of NTA in the SHR occurred from 1 month of age and was observed throughout their life span. The titers of the autoantibody varied among individual rats and progressively increased with age. The NTA was cytotoxic for thymocytes but weak or negative for spleen, lymph node and bone marrow cells. However, absorption test indicated that NTA-reactive antigens were distributed in the thymus, spleen, lymph nodes, and brain of adult rats. The NTA in SHR was an IgM-globulin as determined by sensitivity to 2-ME treatment and by Sephadex G-200 column chromatography. These results suggest that the NTA is responsible for the selective suppression of T-cell functions in SHR.