Cyclophosphamide and lymphocyte subpopulations in Wegener's granulomatosis

Abstract

In 10 patients with Wegener's granulomatosis, low doses of cyclophosphamide produced: severe lymphocytopenia of long duration even after therapy ceased; a greater percentage decrease in nonrosette forming lymphocytes than in rosette forming 1-lymphocytes; normal in vitro lymphocyte responses to mitogens (PHA, ConA, and PWM) with suppressed responses to one of two antigens tested (SK-SD). This regimen did not cause severe granulocytopenia and was successful in inducing and maintaining long-term clinical remissions.Cyclophosphamide is an alkylating agent with well-established immunosuppressive effects in animals and man (1,2). It has been used with therapeutic success in a variety of diseases, such as systemic lupus erythematosus (54) rheumatoid arthritis (5,6) and other inflammatory connective tissue disorders (7). in which autoimmune or immunologic phenomena are thought to play a predominant role.Wegener's granulomatosis (WG) serves as an excellent model of a diffuse hypersensitivity disease in humans (8). It characteristically begins with an inflammatory process in the nasopharynx and paranasal sinuses and progresses to granulomatous vasculitis of the upper and lower respiratory

Lymphopenia and Treatment-Related Infectious Complications in ANCA-Associated Vasculitis

“…However, little data exist regarding the effect of lymphopenia in AAV. Lymphopenia is a well known adverse effect of immunosuppressive therapy (27)(28)(29), and its presence has been proposed as a surrogate for treatment efficacy (30,31) and clinical activity (32). Absolute lymphopenia, induced by the underlying disease or by the immunosuppressive therapy, can reflect different immunologic deficits, which are associated with specific type of infections (e.g., viral and fungal infections in T cell lymphopenia and encapsulated bacteria-related infections in B cell lymphopenia with antibody deficiency).…”

Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells.

“…but unaltered in patients with vasculitic diseases (13, 15) treated with CY. Blastogenic responses to T cell antigens (13,14) and induction ofdelayed hypersensitivity responses to a new antigen (14) can be suppressed during chronic therapy with CY. In contrast, impairment of concanavalin A-inducible suppressor activity and potentiation of delayed-type hypersensitivity responses to a new antigen have been reported (32,33) several days after a single dose of CY.…”

“…Patients were studied between 1.5 and 132 moaftercompletion oftheCYtherapy. 13 In some experiments, the TCD fractions were further monocyte depleted as described previously (23), with slight modification. Briefly, UF mononuclear cells were suspended in 0.2% FCS in RPMI and incubated at 370C for 30 min to allow adherence to 4-mm glass beads (Kimble Div., Owens-Illinois Inc., Toledo, OH).…”

“…This therapeutic approach has been particularly effective in the treatment of a number of systemic vasculitic syndromes including Wegener's granulomatosis (4), systemic necrotizing vasculitis (5), and lymphomatoid granu-lomatosis (6). Although a variety ofimmunomodulatory effects have been demonstrated in animal models after short-term highdose CY treatment protocols (7)(8)(9)(10)(11), information on the effects of chronically administered low-dose CY on the immune system in man is limited (12)(13)(14)(15)(16). Recently, we have demonstrated a clear-cut selective effect of CY therapy on mitogen-stimulated Ig production (16).…”

Cyclophosphamide suppression of established cell-mediated immunity. Quantitative vs. qualitative changes in lymphocyte populations.

“…Recent studies have shown that the activity of certain diseases improved by CY is associated with a reduction of lymphocyte numbers, but not with a detectable depression of mitogen-induced lymphocyte proliferation (22,23). These studies, in conjunction with the findings of the present report, caution that the adequacy of immunosuppressive therapy with CY may not be safely monitored by tests of in vitro mitogen responses of lymphocytes, since doses of CY which suppress these lymphocyte functions may be associated with potential compromise of host defense mechanisms by increasing the risk of development of significant neutropenia.…”