Interleukin-2 (IL-2), the first of a series of lymphocytotrophic hormones to be recognized and completely characterized, is pivotal for the generation and regulation of the immune response. A T lymphocyte product, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2-T cell system has opened the way to a molecular understanding of phenomena that are fundamental to biology, immunology, and medicine.

https://science.sciencemag.org/content/sci/240/4856/1169.full.pdf

Interleukin-2: inception, impact, and implications.

Publisher Summary This chapter reviews the histopathologic, serologic, lymphocytic, virological, hormonal, and genetic characteristics of murine models of systemic lupus erythematosus (SLE). The pathogenetic mechanisms underlying murine SLE are highly complex, apparently well-programmed genetically, but still diverse and their bases not as yet well defined. Significant serologic and cellular experimental data support the statement that the final immunopathologic perturbation in murine (and human) SLE is a B lymphocyte hyperactivity with corresponding enhancement of serum antibodies and autoantibodies, particularly IgG, and consequent formation of pathogenic antigen–antibody ICs. On the basis of the available data, it appears that this B cell hyperactivity is polyclonal but not necessarily panclonal in nature, because not only antibodies against a wide array of autoantigens but also antibodies against incidental antigens, such as haptens, can be detected. The presence of autoantibodies and of their idiotypes in some recombinant lupus x normal murine lines expressing the normal partner's V genes, normal mice in which an exogenous or endogenous (Ipr gene) immunostimulator has been introduced, and unmanipulated normal mice indicate that lupus mice are not unique in their structural genetic Ig elements, whose presence determines the development of their autoimmune disease. The cause of B cell hyperactivity in lupus has not yet been fully elucidated. Autonomous B cell maturation does not appear likely, because B cell proliferation and differentiation in lupus mice was found to be dependent on the same number of accessory signals as in normal mice.

Murine models of systemic lupus erythematosus.

The anti-Tac monoclonal antibody is known to bind to the p55 chain of the human interleukin 2 receptor and to inhibit proliferation of T cells by blocking interleukin 2 binding. However, use of anti-Tac as an immunosuppressant drug would be impaired by the human immune response against this murine antibody. We have therefore constructed a "humanized" antibody by combining the complementarity-determining regions (CDRs) of the anti-Tac antibody with human framework and constant regions. The human framework regions were chosen to maximize homology with the anti-Tac antibody sequence. In addition, a computer model of murine anti-Tac was used to identify several amino acids which, while outside the CDRs, are likely to interact with the CDRs or antigen. These mouse amino acids were also retained in the humanized antibody. The humanized anti-Tac antibody has an affinity for p55 of 3 x 10(9) M-1, about 1/3 that of murine anti-Tac.

https://www.pnas.org/content/pnas/86/24/10029.full.pdf

A humanized antibody that binds to the interleukin 2 receptor.

The autosomal recessive lpr and gld genes induce in mice multiple autoantibodies and the progressive accumulation of large numbers of non-malignant CD4- CD8- T lymphocytes. The clinical syndromes and immune abnormalities associated with these two nonallelic genes are nearly identical and are also highly dependent on background genes. MRL/lpr mice are particularly severely affected, and they develop a syndrome that is serologically and pathologically similar to human systemic lupus erythematosus (SLE). Abnormal cell marker expression in the aberrant lpr T lymphocytes includes surface antigens normally associated with activated T cells or even with B cells, and it occurs along with enhanced expression of certain oncogenes. The lpr gene results in intrinsic abnormalities of both T and B lymphocytes, yet its location and product are unknown. The gld gene is located on chromosome 1; its product is also unknown. Although many immunological abnormalities are known, the mechanism whereby these two genes induce au...

Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease.

Exacerbations of multiple sclerosis in patients treated with gamma interferon

Because TNF and IL-1 can initiate immunologic and inflammatory events alone or synergistically, a local increase in the levels of one or both of these cytokines in vivo may cause irreparable tissue damage. The purpose of this study was to evaluate local TNF and IL-1 beta gene expression in vivo in the kidneys of MRL-Ipr mice with autoimmune lupus nephritis. TNF mRNA was detected in the renal cortex of MRL-Ipr mice but was not present in the cortex of normal congenic MRL-++ or C3H/FeJ mice. MRL-Ipr mice with lupus nephritis expressed higher amounts of TNF mRNA compared with MRL-Ipr mice prior to disease. In addition, freshly isolated, unstimulated glomeruli from MRL-Ipr mice with nephritis were found to secrete detectable levels of TNF, whereas glomeruli from MRL-++ mice did not. IL-1 beta mRNA, present in the renal cortex of C3H/FeJ, MRL-++, and young MRL-Ipr mice with normal kidneys, was also more abundantly expressed in MRL-Ipr mice with nephritis. Cultured macrophages from glomeruli of mice with nephritis were found to express TNF and IL-1 beta mRNA and product. These macrophages are prominent only in MRL-Ipr mice with renal disease and are the likely source of increased gene expression for both cytokines.

Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis.

TNF and IL-1 are potent immunologic and inflammatory cytokines. We have previously reported increased levels of mRNA for TNF alpha and IL-1 beta in MRL-lpr mice with lupus nephritis. To determine whether the increased levels of TNF and IL-1 mRNA are a more general feature of mice with lupus nephritis we studied cytokine gene expression in female NZB x NZW F1 (NZB/W) mice by Northern blot analysis. Enhanced steady state levels of mRNA for TNF alpha and IL-1 beta, but not IL-1 alpha, were detected in the renal cortices of animals with lupus nephritis. To determine whether administration of TNF or IL-1 would accelerate renal injury and mortality, we injected murine rTNF alpha or rIL-1 alpha i.p. into female NZB/W or C3H/FeJ mice at two doses, 2.0 micrograms or 0.2 micrograms, three times weekly for 2 or 4 mo beginning at 2 or 4 mo of age. Administration of the lower dose of each cytokine accelerated renal disease and mortality rate when treatment was initiated at 4 mo of age. At the higher dose, neither cytokine promoted disease. Treatment administered from 2-4 mo of age did not accelerate renal disease. This observation suggests that in order to cause renal injury, these cytokines must interact with other pathologic features present in these animals after 4 mo of age. These findings support the hypothesis that TNF and IL-1 can contribute to nephritis in murine models of lupus. Taken together with previously published data, we propose that TNF and IL-1 have differential dose effects on renal disease. The dose of TNF and IL-1 and the stage of disease activity dictate the pathogenic action of these cytokines.

Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury.

https://www.kidney-international.org/article/S0085-2538(15)34808-0/pdf

MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells.

Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein regulating interactions among immune cells. To determine whether altered expression of ICAM-1 occurs in autoimmune lupus nephritis, we studied ICAM-1 expression in kidneys of normal and autoimmune MRL-lpr and (NZBX NZW)F1 (NZB/W) mice. By immunoperoxidase staining, ICAM-1 is constitutively expressed at low levels in proximal tubules (PT), endothelium and interstitial cells in normal C3H/FeJ mice. In nephritic MRL-lpr and NZB/W kidneys, staining for ICAM-1 is increased in the PT, particularly in the brush border, and is prominent in the glomerular mesangium and the endothelium of large vessels. By Western blot analysis, ICAM-1 is not detected in the urine of normal BALB/c and C3H/FeJ or autoimmune MRL-lpr. By Northern blot analysis, nephritic MRL-lpr and NZB/W have a two- to fivefold increase in steady state levels of ICAM-1 transcripts in the kidney as compared with normal or prenephritic mice. This is paralleled by an increase in MHC class II transcripts. In cultured PT cells, ICAM-1 is expressed at basal levels in PT and is increased by the cytokines interferon-gamma, IL-1 alpha, and TNF-alpha. Thus cytokine-mediated upregulation of ICAM-1 in lupus nephritis may promote interaction of immune cells with renal tissue. The predominant apical expression of ICAM-1 opposite to the basolateral Ia expression suggests a novel role for this adhesion molecule in PT.

Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated in autoimmune murine lupus nephritis.

Administration of the monoclonal antibody M7/20, which binds to the murine interleukin-2 (IL) receptor, significantly prolongs cardiac allograft survival in two H-2-incompatible strain combinations of inbred mice. The results support the important role of the IL-2 receptor in the mechanism of graft rejection, and suggest its suitability as a target for immunosuppressive therapy.

/pdf/administration-of-an-anti-interleukin-2-receptor-monoclonal-2dqo4kglty.pdf

Vicki E. Kelley

Papers

Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis.

Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury.

MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells.

Intercellular adhesion molecule-1 (ICAM-1) expression is upregulated in autoimmune murine lupus nephritis.

Administration of an anti-interleukin 2 receptor monoclonal antibody prolongs cardiac allograft survival in mice