`
`Volume 14
`No. 1 - 1980
`July
`
`An International Jour-nal
`
`GJ
`Dustri-Verlag
`Dr. Karl Feistle
`MGnchen(cid:173)
`Deisenhofen
`
`
`
`Volume 14
`
`G.!
`Dustri-Verlag
`Dr. Karl Feistle
`Munchen(cid:173)
`Deisenhofen
`
`
`
`1:
`'
`I ,,
`
`ctn1cal nephrology
`
`EDITOR-IN-CHIEF:
`
`R. Kluthe, Freiburg
`
`EDITORS:
`
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`© 1980 DUSTRI-VERLAG Dr. Karl Feistle,
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`
`Clinical Nephrology, Vol. 14 No. 5-1980 (pp. 233-237)
`
`The effects of azathioprine and prednisolone on
`T- and 8-lymphocytes in patients with lupus
`nephritis and chronic glomerulonephritis
`I.E. TAREYEVA, E. M. SHILOV arid N. B. GoRDOVSKAYA
`
`Laboratory of N ephrology and Clinic of Internal Medicine, 1st Moscow Medical Setchenov's
`Institute, 11 a Rossolimo str., 119021 Moscow, USSR
`
`Abstract. The effects of long-term treatment with azathioprine and prednisolone on T- and
`B-lymphocytes were studied in 52 patients with lupus nephritis (LN) and chronic
`glomerulonephritis (GN). The effect of azathioprine on lymphocyte populations was dose
`dependent; high doses decreased the number of T- and particularly, B-cells, while smaller
`doses produced a selective depletion of B-cells. The changes in T- and B-cells during
`prednisolone treatment were variable with alternating increases and decreases in their
`numbers. The patients with increased B-lymphocyte levels showed the best response to
`immunosuppressive therapy.
`
`The effects produced by immunodepressants
`upon the T- and B-lymphocyte systems are important
`because of the different effector mechanisms of
`humoral and cellular immunity in the pathogenesis of
`certain autoimmune diseases. The anti-proliferative
`effect of cyclophosphamide is known to be more
`pronounced on B-lymphocytes. With azathioprine the
`findings appear to be conflicting.
`
`The therapeutic efficacy of corticosteroids and
`cytostatics is generally associated with inhibition of
`immunological reactions (in addition to nonspecific
`anti-inflammatory action), thus leading to their use in
`patients with high immunological activity. The corre(cid:173)
`lation between the level of T-lymphocytes and disease
`activity in systemic lupus erythematosus (SLE) is well
`documented [Schelnberg and Cathcart 1974, Hamil(cid:173)
`ton and Winfield 1979], while the data concerning B(cid:173)
`lymphocytes is conflicting [Messner et al. 1973,
`Arimori et al. 1975, Sandhofer et al. 1975]. The same
`applies to T- and B-cell numbers in patients with
`glomerulonephritis [Tishkov et al. 1976, Zucchelli et
`al. 1976]. Thus further studies of the T- and B-cell
`levels in SLE and GN patients are warrented.
`
`The present study was designed to: 1) reveal
`correlations between numbers of T- and B-cells and
`disease activity in lupus nephritis (LN) and chronic
`GN; 2) study the effect of long-term therapy with
`azathioprine and prednisolone on T- and B-cells in
`LN and GN patients; 3) evaluate the dependence of
`
`Received January 31, 1980, in revised form April 24, 1980.
`Reprint requests to Dr. I. E. T areyeva.
`
`the efficacy of treatment on the initial T- and B-cell
`levels.
`
`Materials and methods
`
`Patients: The levels of T- and B-lymphocytes
`were studied in 110 patients (70 with GN and 40 with
`LN) aged 15 to 57 years and in 33 age- and sex(cid:173)
`matched normal subjects. The effect of azathioprine
`and prednisolone on T- and B-lymphocytes was
`studied in 52 LN and GN patients.
`Fifty-eight patients had chronic GN and 12
`patients had acute poststreptococcal GN. Renal
`biopsy specimens were obtained in 37 patients with
`chronic GN: 11 had mesangio-proliferative GN, 5-
`inesangio-membranous, 6-membranous GN, 2-
`mesangio-capillary GN, 2-lobular GN and 11-fibro(cid:173)
`plastic GN. Immunofluorescence was studied in 28
`cases: IgG was demonstrated in glomeruli in 18 cases,
`IgM - in 6, IgA - in 3 and fibrin - in 4 cases.
`At the time of study, 15 of the 40 LN patients
`had active SLE with nephritis and multiple systemic
`signs, 13 had active LN without extrarenal manifesta(cid:173)
`tions and 12 had inactive disease. Renal biopsy (21
`patients) revealed diffuse proliferative LN in 6
`patients, focal proliferative - in 8, membranous - in 2
`and fibroplastic - in 5. IgG was found in glomeruli in
`12 out of 16 cases studied by immunofluorescent
`methods.
`At the start of the study 103 out of 110 patients
`were receiving no immunodepressive drugs; 7 patients
`with active SLE were receiving low doses of pred(cid:173)
`nisolone (5-15 mg/day).
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`234
`
`Tareyeva, Shilov and Gordovskaya
`
`The effect of azathioprine was studied in
`12 patients (2 with LN and 10 with GN), whereas that
`of prednisolone was studied in 28 patients (18 with
`LN and 10 with GN); a combination of azathioprine
`and prednisolone was studied in 12 patients (2 with
`LN and 10 with GN). During the first month of
`treatment investigations were carried out every 7 days
`and from the second month of treatment every 3--4
`weeks.
`In order to exclude the possibility of spontaneous
`variations in T- and B-cell level, studies were repeated
`(2 to 6 times) for 2 to 64 weeks in 6 healthy donors
`and in 15 LN and GN patients who were not given
`any immunosuppressive agents.
`Lymphocytes were isolated from heparinized
`venous blood using a Ficoll-Hypaque gradient. The
`resulting suspension contained 85-90% lymphocytes
`with viability greater than 95% as assessed by trypan
`blue exclusion. Monocytes were detected by incubat(cid:173)
`ing mononuclear cells with latex particles.
`B-lymphocytes were counted after immuno(cid:173)
`fluorescent labelling of membrane-bound immuno(cid:173)
`globulin. The cells were incubated at 37° for 30
`minutes before the addition of fluorescent antiserum
`to eliminate serum IgG fixed to Fe receptors and
`antilymphocyte antibodies. This allowed the exclusion
`of cells having receptors for Fe fragmentes of IgG
`[Lobo et al. 1975] so that only B-lymphocytes were
`counted. Under these conditions the mean percentage
`of lg-bearing B-lymphocytes in normal subjects was
`9.7 ± OA%.
`
`T-lymphocytes were studied by the E-rosette
`formation technique using sheep erythrocytes (SRBC)
`[Jondal et al. 1972], without pretreatment of SRBC
`with neuraminidase and without the addition of serum
`to lymphocyte and erythrocyte suspensions. Lym(cid:173)
`phocytes which did not . carry membrane-bound
`immunoglobulins and which did not form E-rosettes
`were designated as null cells [Froland et al. 1974]. The
`percentage of E-rosette forming cells (51.4 ± 2.3%)
`the
`was lower than that usually described, and
`percentage of O-cells was higher and included a small
`number of T-cells.
`
`Results
`
`The numbers of T- and B-lymphocytes ip. LN
`and GN patients are presented in Table 1. During
`exacerbation of disease the proportion of B-lympho(cid:173)
`cytes in all groups of patients increased with simul(cid:173)
`taneous reduction of the proportion of T-cells. These
`changes were most marked in patients with active SLE
`(B-19.7 ± 2.0%; T-29.3 ± 3.1 %) who also had an
`increased percentage of null lymphocytes (51.0 ±
`3.4%).
`Absolute numbers of T- and B-lymphocytes also
`reflected the activity of disease, but contrary to the
`percentage counts, differed in GN and LN. Most GN
`patients had a lymphocytosis with an increased abso(cid:173)
`lute number of B- and null lymphocytes, and a normal
`T-cell count. On the contrary, in patients with active
`
`Table 1 Levels of B-. T-, O-cells and total lymphocyte count in GN and LN patients before treatment (mean ± SD).
`
`Patients
`
`Lymphocytes
`Total
`number
`
`B
`%
`
`mm3
`
`T
`%
`
`Acute GN
`
`(n= 12)
`
`2343±352
`P<0.02''
`
`12.9±1.8
`<0,02
`
`256±28
`<0.01
`
`39.8±4.5
`<0.05
`
`mm3
`
`840±102
`
`0
`%
`
`mm3
`
`47.3±5.4
`>0.05
`
`1284±218
`<0.01
`
`Chronic GN:
`active
`
`inactive
`
`LN:
`with systemic
`lesions
`
`(n = 15)
`
`isolated
`
`(n= 13)
`
`in remission
`
`(n= 12)
`
`Normals
`
`(n=33)
`
`(n = 39) 2144±154
`P<0.05
`1704± 154
`
`(n= 19)
`
`16.5 ±1.1
`<0.01
`9.2±0.9
`
`356±32
`<0.01
`153± 17
`>0.1
`
`93±10
`<0.01
`250±30
`<0.01
`140±17
`<0.1
`173± 11
`
`42.8±2.8
`<0.05
`48.0±3,1
`
`865±108
`
`41.6±2.6
`
`824±96
`
`44.043.2
`
`29.3±3.1
`<0.01
`35,3±3,2
`<0.01
`44.3±4.0
`>0.1
`51.4±2.3
`
`156±26
`<0.01
`582±77
`<0.02
`621±78
`<0,05
`844±60
`
`51.0±3.4
`<0.05
`48.8±3.9
`>0.05
`46.1 ±4.1
`>0.1
`41.6±2.4
`
`984±82
`<0.01
`779±97
`>0.1
`
`263±35
`<0.01
`782±83
`>0.1
`672±76
`
`682±17
`
`505±44
`P<0.01
`1569± 177
`P>0.1
`1430±90
`P<0.01
`1764±70
`
`19.7±2.0
`<0.01
`17.1 ±2.4
`<0.01
`9.6±2.9
`>0.1
`9.7±0.4
`
`* P values are for comparison with normals.
`
`
`
`The effects of azathioprine and prednisolone on T- and B-lymphocytes
`
`235
`
`• - B-cells
`o-- T-cells
`+----- 0-cells
`
`200
`days
`
`200[
`0 ~ - - - - - - - - - - - - - - - - '
`Azathiopzine
`mg/day
`
`Fig. 1 The effects of azathioprine on B-, T- and null-lymphocytes
`in 12 patients (LN-2, Chronic GN-10).
`
`prednisolone alone, i.e. there was an increase in T(cid:173)
`and B-cells in some patients and a decrease in others,
`depending on the initial levels. Later, lymphopenia
`developed which, from the third month, became
`selective in respect to B-cells.
`Some changes in T- and B-cell levels were
`observed in long-term studies in 6 healthy donors and
`15 patients receiving no immunodepressive drugs, but
`the variations were less marked. The magnitude of the
`variations expressed as a mean standard deviation for
`T-cells was: ± 96/mm3 in donors and ± 67 /mm3 in
`untreated patients;
`the same values for B-cells
`were ± 36/mm3 and 51/rnml, and were statistically
`lower (P<0.01) than the variations in the pred(cid:173)
`nisolone-treated patients (T-cells: ± 670/mm3 in GN
`patients and ± 299/mm3 in LN patients; B-cells:
`±318 and ± 252/mm3
`).
`The efficacy of treatment was analyzed in 26 LN
`and GN patients treated for a long time with adequate
`doses of azathioprine or prednisolone. In patients
`showing a good response to treatment the initial level
`oI B-lymphocytes was found to be significantly higher
`than .in those whose treatment was ineffective (fig. 3).
`The efficacy of treatment did not depend on the initial
`level of T-lymphocytes.
`
`Discussion
`
`The study of lymphocyte populations revealed a
`clear-cut correlation between the level of T- and B(cid:173)
`cells and disease activity in patients with LN and GN.
`In both diseases the proportion of B-lymphocytes was
`increased during periods of activity with simultaneous
`reductions of T-cells. However, the absolute numbers
`of T- and B-cells differed significantly in LN and GN.
`The patients with active GN had an increased number
`
`400
`
`1000
`
`C'l
`
`U)
`
`E
`E
`--..
`'ij5 500
`<J
`I-
`"O
`C:
`
`"' 0
`
`200
`..,E
`E
`--..
`.!'!
`ai
`
`(J
`ID
`
`0
`
`30
`
`100
`
`100 [ .--L..... ___ __J
`
`SLE, lymphopenia (505/mm3
`) developed due to a
`decrease in all lymphocyte populations, particularly
`T-cells (156/m.m3
`). In patients with active LN without
`extrarenal signs the absolute number of B-lympho(cid:173)
`cytes was elevated (250/mm3
`) and that of T-cells was
`decreased (528/mm3
`), the total lymphocyte count
`being normal.
`The effect of azathioprine was studied in
`2 patients with LN and in 10 with chronic GN. The
`mean daily drug dosage during the first mo~th was
`-150 mg, being lower during the second and third
`months (90 mg). In 4 patients who were treated for
`more than 3 months the dosage was increased again
`(170 mg/day on the average). By the end of the first
`month of treatment the total number of lymphocytes
`bad decreased by 39% and in 6 months by 63%.
`The sensitivity of the different lymphocytic
`populations to the cytopenic effect of azathioprine
`varied (fig. 1). By the end of the first month of
`treatment the absolute number of B-cells was reduced
`by 50% and that of T-cells by 38%. In the course of
`further treatment with lower doses, the B-cell content
`continued to fall, while the number of T-lymphocytes
`returned to the initial level. An increased dose of
`azathioprine in the 6th month resulted in a further
`drop in the B-cell level and in a new fall in the T(cid:173)
`lymphocyte level (by 87.5% and 69% form the initial
`levels, respectively).
`The proportions of B- and null lymphocytes
`changed during the course of treatment: B-cells were
`reduced from 14.9% to 4.6% whereas the proportion
`of null lymphocytes increased from 42.02% to 56.5%.
`The percentage of T-cells during the same period
`remained virtually unchanged (43.1 % and 46.8%).
`The effect of prednisolone (20-60 mg daily, aver(cid:173)
`age 45 mg) was studied in 28 patients during treatment
`lasting 4-12 weeks. In contrast to the dear-cut results
`obtained with azathioprine, the changes in T- ind B(cid:173)
`lymphocy:.t~s were not uniform,
`their numbers
`increasing and decreasing cyclically. At the start of
`treatment the changes in T- and B-cell numbers
`depended on their initial levels. The patients with
`relatively bigh initial levels of T- and B-cells showed a
`decrease in their numbers, while those with relatively
`low initial levels showed an increase.
`The number of lymphocytes tended to increase in
`the patients with active SLE (whose initial T- and B(cid:173)
`cell levels were markedly decreased), the growth rate
`being higher for 13-lymphocytes than for T-cells
`(fig. 2). In the GN patients the number of T- and B(cid:173)
`lymphocytes were, however, near to or below the
`initial level showing similar fluctuations.
`In the course of combined treatment with
`azatbioprine and prednisolone (12 patients), the
`changes in T- and B-lymphocytes during the first
`month resembled those seen during treatment with
`
`
`
`236
`
`1500
`
`1000
`
`500
`
`-500
`
`500
`
`-500
`
`Tareyeva, Shilov and Gordovskaya
`
`T-lymphocytes
`(per mm3)
`
`8-lymphocytes
`(per mm 3)
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`Fig. 2 The effects of prednisolone
`on B- and T-lymphocyte counts in
`18 LN patients
`(with
`systemic
`isolated LN-6 ).
`lesions
`-
`12,
`Changes in lymphocyte counts in
`relation to baseline levels.
`
`100
`days
`
`of B- and null lymphocytes with a normal T-cell
`count, leading to lymphocytosis. In active SLE, lym(cid:173)
`phopenia developed due to decrease in all lymphocyte
`populations, particularly in T-cells. However, in
`patients with "isolated" active LN with the charac-
`
`B-cells
`per mm 3
`500
`
`400
`
`300
`
`200
`
`100
`
`Pr
`
`Az
`
`Normals
`
`Fig. 3 The correlation between the efficiency of azathioprine (Az)
`and prednisolone (Pr) treatment and the initial B-cell level in
`patients with GN and LN ( ■-initial B-cell numbers in patients with
`effective treatment. mil-initial B-cell numbers in patients with
`ineffective treatment. O-B-cell levels in normals subjects.
`
`teristic low T-cell level of SLE, the absolute number of
`B-lymphocytes was increased, as in chronic GN.
`Our findings demonstrate a decrease in the
`relative and absolute numbers of T-lymphocytes in
`active SLE with a simultaneous increase of the per(cid:173)
`centage of B-cells which agrees with the reported data
`[Messner et al. 1973, Hurd and Giuliano 1975]. Data
`about the absolute number of B-lymphocytes are
`conflicting. We observed a reduced absolute number
`of B-lymphocytes in patients with active SLE, as did
`Messner et al. [1973], Hurd and Giuliano [1975] and
`Hamilton and Winfield [1979]. However, some work(cid:173)
`ers report normal [Sandhofer et al. 1975] or increased
`levels [ Arimori et 1. 1975] of this lymphocyte popula(cid:173)
`tion in patients with SLE.
`Zucchelli et al. [1976] found a reduced percentage
`of T-lymphocytes in GN patients which agrees with
`our fingings. They failed to observe, however, changes
`in the percentage of B-lymphocytes with lg receptors.
`The predominant effect of azathioprine upon T(cid:173)
`or B-cell population has been debated at length.
`Experimental findings showing a prevailing effect
`upon B-lymphocytes [Winkelstein 1973] have not
`been previously confirmed in patients [Yu et al. 1974,
`Campbell et al. 1976]. According to our data, treat(cid:173)
`ment with azathioprine resulted in variable depression
`of the different lymphocyte populations; the degree of
`lymphopenia depended on the duration of treatment
`
`
`
`The effects of azathioprine and prednisolone on T- and B-lymphocytes
`
`237
`
`and the dosage employed. Higher doses of azathio(cid:173)
`prine decreased the numbers of B-cells and, to a lesser
`extent, of T-celis; smaller doses resulted in selective
`inhibition of the B-cell population, which supports
`experimental data of a greater sensitivity of B-ceUs to
`the antiproliferative effect of azathioprine [Winkel(cid:173)
`stein 1973].
`Predominant development of B-cell lymphopenia
`during long-term administration of azathioprine may
`be associated with a shorter life-span of t~s popula(cid:173)
`tion compared to that of the thymus-dependent
`lymphocyte population.
`A series of mechanisms underlies the immuno(cid:173)
`suppressive action of prednisolone, the most relevant
`being interference with the processes of migration and
`circulation of lymphocytes [Petrov et al. 1975]. How(cid:173)
`ever,
`the effect produced by corticosteroids on
`peripheral blood T- and B-ceils during long-term
`administration have not been adequately studied,
`occasional clinical observations being very conflicting
`[Yata et al. 1975, Jonsson 1975].
`We observed wave-like changes in T- and B-cell
`numbers in peripheral blood that depended on the
`initial levels of lymphocyte populations: in the initial
`phase of treatment, numbers of T- and B-cells
`decreased in patients with relatively high initial levels
`and increased in those with relatively low initial levels.
`In view of the fact that healthy donors and
`untreated patients exhibited some variations in T- and
`B-cell levels we compared the magnitude of these
`variations with those seen in patients in the course of
`their treatment. The comparison revealed a signifi(cid:173)
`cantly higher degree of variation in patients who were
`treated with prednisolone. This enables us to relate
`large variations in the T- and B-cell levels during
`treatment to the eHect produced by prednisolone.
`These changes are likely to be associated with the
`action of prednisolone upon the migration and circu(cid:173)
`lation of lymphocytes [Petrov et al. 1975].
`The best results of treatment with azathioprine
`and prednisolone were observed in LN and GN
`patients with
`increased B-lymphocyte levels
`in
`peripheral blood which, according to Lueker et al.
`[1975], reflects an intensive humoral immune response
`accompanied by proliferation of a B-lymphocyce
`clone.
`
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`