Changes in T-cell subsets in patients with rheumatoid arthritis treated with total lymphoid irradiation

doi:10.1016/0090-1229(83)90075-2

Clinical Immunology and Immunopathology

Volume 27, Issue 2, May 1983, Pages 250-260

Clinical Immunology ...

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Abstract

Patients with intractable rheumatoid arthritis (RA) were treated with total lymphoid irradiation (TLI, 2000 rads). We previously reported long-lasting clinical improvement associated with marked suppression of in vitro lymphocyte function in this group. In an attempt to better understand the mechanism of immunosuppression and clinical changes observed after TLI, we studied in greater detail changes in peripheral blood T-cell subsets identified by monoclonal antibodies. Before TLI, RA patients had a higher percentage of Leu-3 (helper subset) cells and a lower percentage of Leu-2 (suppressor/cytotoxic subset) cells than normals. Immediately after TLI, the absolute numbers of both Leu-2 and Leu-3 cells were reduced by at least 90%. Within 6–12 weeks, the number of Leu-2 cells returned to the pretreatment levels, but the levels of Leu-3 cells remained depressed for months thereafter. The lack of repopulation of Leu-3 cells resulted in a marked increase in the ratio of Leu-2 to Leu-3 cells as compared to pretreatment values (1.73 ± 0.23 vs 0.39 ± 0.06), and in a decrease in the percentage and absolute number of total T (Leu-1 and Leu-4) cells. The failure of Leu-3 cells (which mediate predominantly helper/inducer functions) to repopulate the peripheral blood may contribute to the prolonged clinical immunosuppression observed after TLI. Similar changes in T-cell subsets were not observed in RA patients given remittive drugs or low doses (200 rads) of radiotherapy. Thus, TLI differs from other treatment modalities with regard to its prolonged selective effect on the Leu-3 subset.

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1997, Journal of the Neurological Sciences
We have monitored the cell surface phenotypic changes occurring in T, B and NK cells of chronic progressive multiple sclerosis (MS) patients after total lymphoid irradiation (TLI) plus low-dose prednisone (TLI-LDP) therapy in comparison to sham TLI-LDP. TLI-LDP resulted in a marked reduction in the relative and absolute number of total CD3⁺ T cells, CD4⁺ helper T cells, CD4⁺CD45RA⁺ naive T cells and CD19⁺ B cells for at least 1 year after treatment. No change occurred in the percent CD8⁺ T cells although the number of these cells declined after radiotherapy. The CD4/CD8 T cell ratio was also decreased. The relative percent of CD16⁺ NK cells increased steadily after TLI-LDP while the number of NK cells transiently declined but returned to baseline values 1 year later. An increase in the percent of CD2⁺CD3⁻ cells and a decrease in their number after therapy was also observed. In contrast, no significant changes in the number of T, B or NK cells were seen in the MS patients receiving sham TLI-LDP. These results provide further evidence that radiotherapy causes a reduction of immunocompetent T and B cells and that a population of possibly NK cells and/or immature T cells appears to be repopulating the circulation after TLI. In addition, a correlation was observed between alterations in lymphocyte populations and the presence or absence of contrast enhancing or new T₂ lesions on brain magnetic resonance imaging (MRI) in the TLI-LDP treated MS patients. Patients devoid of contrast enhancing or new T₂ lesions had a decreased percentage of CD3⁺ and CD4⁺ T cells prior to therapy and at six months following TLI-LDP compared to patients with such lesions. An association was also observed between stability in disease activity as determined on the Expanded Disability Status Scale and relative values of CD3⁺ T cells.
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Total lymphoid irradiation (TLI) is effective in the immunosuppressive treatment of human and experimental autoimmune disorders, including experimental autoimmune myasthenia gravis (EAMG). Under certain circumstances, TLI may facilitate the induction of specific tolerance to antigens present during or shortly after the TLI treatment. This study was designed to determine whether TLI could induce or enhance tolerance to acetylcholine receptor (AChR), the antigen in myasthenia gravis, or to other antigens. We presented the antigens in various potentially tolerogenic forms to rats that were first pre-treated with TLI, or controls treated with sham irradiation. Injection of deaggragated human gamma globulin (HGG), a classical tolerogen, was most effective; it produced antigen-specific tolerance, which was significantly enhanced by pre-treatment with TLI. Injection of HGG coupled to rat peritoneal cells induced a moderate degree of specific tolerance; in this case, pre-treatment with TLI added only nonspecific suppression. In contrast, AChR, either in solubilized form with no adjuvant, or coupled to syngeneic rat pertoneal cells, failed to induce tolerance, and actually primed to immune system system, when given alone or in conjunction with TLI. Subsequent challenge with AChR resulted in an enhanced (secondary) anti-AChR antibody response.
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The ability of an anti-CD3 monoclonal antibody (OKT3) to induce proliferation was examined in peripheral blood mononuclear cells (PBM) from 30 patients with rheumatoid arthritis (RA). Controls consisted of 10 patients with osteoarthritis, 12 patients with psoriatic arthritis, and 12 healthy subjects. The results revealed enhanced PBM reactivity in patients with active RA relative to inactive RA patients and all control groups. PBM of patients with mild/moderate clinical disease activity exhibited augmented anti-CD3 reactivity while those with severe disease demonstrated impaired reactivity. Enhanced reactivity was also observed in the active RA group using another anti-CD3 monoclonal antibody (Leu-4). Differences in anti-CD3 dose-response or time kinetics could not account for the results. Studies of enriched T-cell preparations revealed a markedly enhanced anti-CD3 reactivity of RA T-cells relative to normal control T-cells. Monocyte/T-cell mixing experiments revealed no enhanced reactivity of RA monocytes in the anti-CD3 response. RA T-cell preparations depleted of monocytes by limiting dilution reacted significantly more to anti-CD3 in the presence of IL-2 relative to controls. The enhanced reactivity could be accounted for in part by hyperreactivity of the OKT8-bearing subpopulation of T-cells.
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For several types of cancers, post-operative radiation therapy is able to reduce the incidence of local recurrences, but has only a relatively small beneficial effect on total survival. Conversely to what has been claimed, this discrepancy is not due to a detrimental effect of radiotherapy. The data do not substantiate the hypothesis that irradiation through an impact on the immune system enhances growth of neoplastic foci located outside of the irradiated volume. Several sets of data show that uncontrolled primary tumors or lymph node metastases can be important foci for distant spread. However the analysis of the data shows that post-operative radiotherapy can prevent metastatic spread only in a small subset of patients, those without distant metastases at the initial treatment and in whom local recurrences can be a nidus for distant dissemination before being detected and treated. The results of the clinical trials carried out on patients with breast cancers show that this situation is frequently observed in patients with tumors located in the inner quadrants of the breast who are those in whom the involvement of the internal mammary chain is relatively frequent.
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Changes in T-cell subsets in patients with rheumatoid arthritis treated with total lymphoid irradiation

Abstract

Lancet

Lancet

J. Clin. Invest.

J. Exp. Med.

J. Exp. Med.

Transplantation (Baltimore)

J. Exp. Med.

J. Immunol.

Arthritis Rheum.

New Engl. J. Med.

J. Immunol.

J. Immunol.

Scand. J. Clin. Lab. Invest.