Inadequate Ability of T-Lymphocytes from Chronic Uremic Subjects to Stimulate the in vitro Growth of Committed Erythroid Progenitors (BFU-E)

Abstract

The growth of normal burst-forming units (BFU-E) is known to depend on a burst-promoting activity (BPA) produced by T-lymphocytes. Few BFU-E colonies have been observed in cultures of blood mono-nuclear cells (MNC) of uremic patients. The aim of the present study was to examine the concentration of BFU-E in the blood of uremic patients and to evaluate the ability of uremic T-lymphocytes to produce BPA. We have studied 6 chronic uremic patients treated with maintenance hemodialysis. When 5 × 10⁵ blood MNC depleted of T-lymphocytes of uremic subjects were stimulated by 1 × 10⁶ normal T-lymphocytes in a methylcel-lulose culture system we observed the growth of a number of BFU-E colonies that did not differ significantly from normal (29 ± 11.8 colonies). On the contrary, when 5 × 10⁵ blood MNC depleted of T-lymphocytes of normal subjects were stimulated by 1 × 10⁶ T-lymphocytes of uremic patients, the number of BFU-E colonies obtained was significantly lower than normal (1.9 ± 3.1 colonies). These data show that the decreased number of BFU-E colonies obtained from blood MNC of uremic patients is due to a defect of uremic T-lymphocytes. The impairment of T-lymphocytes can be due to inhibitors of T-lymphocyte function or to variations in T cell subsets, leading to a decrease in the OKT₄/OKT₈ cell ratio. In any case it is a significant pathogenetic mechanism contributing to anemia in chronic uremia.

Recombinant Human Erythropoietin: Physiology, Pathophysiology of Anemia in Renal Failure, and Economic Aspects Related to Dosing

“…In such cases, parenteral iron may be required. Marrow suppression from yet-to-be-identified inhibitors working on committed erythroid precursors (colony-forming units-erythrdid) at an earlier stage of their development (as burst forming units-erythroid) is a real phenomenon [41,42]. Studies have shown that plasma from uremic individuals inhibits both heme syn thesis [43] and erythroid stem-cell proliferation in vitro [44.45].…”

Inhibition of BFU-E in vitro Growth and of Burst-Promoting Activity of T Lymphocytes by Serum of Chronic Uremic Patients Receiving Hemodialysis

“…In vivo inhibition of BFU-E by uremic toxins seems then to be one of the mechanisms of anemia in chronic uremia. However the inhibition seems to be reversible, as previous results showed that blood BFU-E responded normally to burst-promot ing activity when removed from the uremic environ ment [1,8]. This observation and the fact that hemodi alysis is able to remove almost completely the serum inhibitor(s), explain why erythropoietin, adminis tered soon after the dialysis is terminated, is able to increase the number of circulating BFU-E and to cor rect the anemia of chronic uremia [11][12][13][14][15][16][17].…”

“…Blood mononuclear cells (MNC) of chronic uremic patients treated with intermittent hemodialy sis have been shown to give rise to normal numbers of BFU-E colonies when stimulated in vitro by normal T lymphocytes [1], On the other hand, T lymphocytes of the same patients were not able to stimulate the growth of normal BFU-E [1]. An imbalance of T cell subpopulations, with reduction of T4 helper-inducer lymphocytes and lowering of the T4/T8 ratio, has also been reported in uremic patients [2].…”

Effect of Cimetidine on Peripheral Blood Lymphocytes from Chronic Uremic Patients: Improvement of Burst-Promoting Activity

“…We have studied the effect of cimetidine on uremic T lymphocytes and on normal T lymphocytes previously in cubated with uremic serum in order to understand why T lymphocytes of uremic patients have a reduced ability to stimulate the in vitro growth of BFU-E [10] and uremic se rum inhibits the BPA of normal T lymphocytes [11]. Nor mal blood T cells are known to contain at least two func tionally distinct subpopulations with opposing regulatory effects: OKT4+ cells enhancing burst formation and OKT8+ cells not producing BPA or even suppressing erythroid growth under specific conditions [27-31], Cime tidine is reported to abrogate the in vitro effects of sup pressor T lymphocytes [13][14][15][16][17][18][19][20], Our study shows that cime tidine is able to increase the BPA of T lymphocytes of ure mic patients.…”

“…However, as data suggest the existence of BPA different from IL-3 [8], at the present time, BPA remains a suitable definition for factor(s) that increase the number or survival of eryth roid burst-forming units (BFU-E) [9], The BPA of T lymphocytes from uremic subjects treated with intermittent hemodialysis has been shown to be significantly impaired [10]. The sera of the same pa tients inhibited the BPA of normal T lymphocytes, hemo dialysis being rather ineffective in removing the serum inhibitor(s) [11], Both total T lymphocytes and the helperinducer subset, identified by OKT4 monoclonal antibod ies, have been found to be significantly lower than normal in uremic subjects, the cytotoxic-suppressor OKT8+ cells being only moderately reduced [12], Cimetidine is re ported both to abrogate the in vitro effects of suppressor T lymphocytes on peripheral blood lymphocyte activation [13][14][15][16][17][18][19][20] and to decrease the in vivo excessive suppressor cell activity [21,22].…”