Janice B. Allen

Transforming growth factor beta 1 suppresses acute and chronic arthritis in experimental animals.

Systemic administration of the cytokine, TGF beta 1, profoundly antagonized the development of polyarthritis in susceptible rats. TGF beta 1 administration (1 or 5 micrograms/animal), initiated one day before an arthritogenic dose of streptococcal cell wall (SCW) fragments, virtually eliminated the joint swelling and distortion typically observed during both the acute phase (articular index, AI = 2.5 vs. 11; P less than 0.025) and the chronic phase (AI = 0 vs. 12.5) of the disease. Moreover, TGF beta 1 suppressed the evolution of arthritis even when administration was begun after the acute phase of the disease. Histopathological examination of the joint revealed the systemic TGF beta 1 treatment greatly reduced inflammatory cell infiltration, pannus formation, and joint erosion. Consistent with the inhibition of inflammatory cell recruitment into the synovium, TGF beta 1 reversed the leukocytosis associated with the chronic phase of the arthritis. Control animals subjected to the same TGF beta 1 dosing regimen displayed no discernable immunosuppressive or toxic effects even after 4 wk of treatment. These observations not only provide insight into the immunoregulatory effects of TGF beta, but also implicate this cytokine as a potentially important therapeutic agent.

Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta.

Monocytes in the circulation of normal individuals express two receptors for the constant region of immunoglobulin, Fc gamma RI and Fc gamma RII. In contrast, we have observed that AIDS monocytes express significant levels of a third Fc gamma R, Fc gamma RIII (CD16), which is normally associated with activation or maturation of the monocyte population. By dual-fluorescence analysis using a monoclonal antibody specific for Fc gamma RIII (MAb 3G8), 38.5 +/- 3.2% of the LeuM3 (CD14)-positive monocytes in AIDS patients were CD16 positive as compared to 10.4 +/- 1.0% for healthy individuals (n = 29; P less than 0.005). Furthermore, AIDS monocytes expressed Fc gamma RIII-specific mRNA which is expressed minimally or not at all in control monocytes. As a recently identified inducer of Fc gamma RIII expression on blood monocytes, transforming growth factor-beta (TGF-beta) was found to be elevated in the serum and/or plasma of AIDS patients. Moreover, incubation of normal monocytes with AIDS serum or plasma induced CD16 expression which correlated with serum TGF-beta levels (r = 0.74, P less than 0.001) and was inhibited with a neutralizing antibody to TGF-beta. Thus, the increased CD16 expression on peripheral blood monocytes in AIDS patients may be the consequence of elevated circulating levels of the polypeptide hormone TGF-beta.

Expression of interleukin 2 receptors by monocytes from patients with acquired immunodeficiency syndrome and induction of monocyte interleukin 2 receptors by human immunodeficiency virus in vitro.

A population of circulating mononuclear cells from patients with AIDS was identified which expressed interleukin 2 receptors (IL-2R). By dual-fluorescence flow microfluorometry, the patients IL-2R+ cells were further identified as Leu M3+ monocytes (29.4 +/- 5.2% of the Leu M3+ cells were IL-2R+, n = 15), whereas Leu M3+ monocytes from normal subjects were IL-2R negative (2.0 +/- 0.42%; P less than 0.001). By Northern analysis, monocytes from AIDS patients, but not control subjects, constitutively expressed steady-state levels of IL-2R mRNA. Functionally, the IL-2R+ monocytes were capable of depleting IL-2 from culture supernatants, suggesting a mechanism for the reduced IL-2 levels commonly seen in AIDS patients. IL-2R+ monocytes also expressed increased levels of surface HLA-DR which may favor monocyte T-cell interactions and the transmission of human immunodeficiency virus (HIV). In additional studies, normal monocytes were infected with a macrophage-tropic HIV isolate in vitro and monitored for IL-2R and HLA-DR expression. Within 24-48 h after exposure to HIV in vitro, but before evidence of productive infection, greater than 25% of the monocytes became IL-2R+ with increasing numbers of IL-2R+ cells and HLA-DR levels through day 6. These early signaling effects of HIV could be mimicked by adding purified HIV envelope glycoprotein gp120 to the monocytes. This stimulation of monocytes before or independent of productive infection of the cells by HIV is consistent with in vivo observations of activated and/or abnormal functions by monocytes that do not appear to be infected with HIV in AIDS patients.

Suppression of bacterial cell wall-induced polyarthritis by recombinant gamma interferon

Group A streptococcal cell wall fragments (SCW) induce erosive polyarthritis, characterized by synovial cell hyperplasia and intense mononuclear cell infiltration, in susceptible rats. Because of the known antiproliferative and immunomodulatory effects of interferon (IFN), we evaluated the effect of systemically administered alpha, beta and gamma IFN on the evolution of these destructive lesions. Treatment with gamma IFN not only reduced the acute response, but had an even greater suppressive effect on the chronic mononuclear cell-mediated destructive phase of the disease (articular index 10.2 +/- 1.2 for SCW only versus 3.8 +/- 0.7 for SCW + gamma IFN; p less than 0.01). Treatment with gamma IFN was more effective in the suppression of the arthritis than alpha, beta IFN. Histopathologic evaluation of the joints demonstrated that gamma IFN-treated animals had significantly fewer inflammatory cells, and less synovial hyperplasia and erosions than the SCW controls. gamma IFN suppression of mononuclear cell prostaglandin synthesis and synovial fibroblast proliferation was consistent with its anti-arthritic effects. These data indicate that the pathophysiology of SCW-induced erosive polyarthritis is subject to regulatory control by gamma IFN and that the mechanisms of suppression may be relevant in the treatment of rheumatoid arthritis.