Cytotoxic T-cell capacity after autologous bone marrow transplantation

A total of 19 patients, treated for aggressive tumors with high-dose chemo/radiotherapy and autologous bone marrow transplantation (BMT), were studied for concanavalin-A (Con A)-induced proliferation and Con-A-induced cytotoxicity. Ten patients with cytomegalovirus (CMV) antibodies before BMT showed increased Con-A-induced cytotoxicity before and from 100 days after BMT, while Con-A-induced proliferation decreased to less than 10% of control values after BMT and remained so. Nine CMV-negative patients showed normal cytotoxic capacity before and after BMT, while Con-A-induced proliferation recovered slowly from day +30 after BMT. Con-A-induced cytotoxicity was not significantly different between CMV-positive and CMV-negative patients, while Con-A-induced proliferation showed significant differences from day +100 onward.     

No predictive value of cytotoxic or helper T-cell precursor frequencies for outcome when analyzed from the graft after stem cell transplantation

The predictive value of limiting dilution analyses (LDA) measuring cytotoxic and helper T-lymphocyte precursor (CTLp and HTLp) frequencies for outcome after stem cell transplantation (SCT) is still a matter of debate. One reason may be that CTLp and HTLp frequencies are determined in peripheral blood mononuclear cells (PBMC) and this responder cell population does not reflect the cell type composition of the graft. We assessed whether CTLp and HTLp LDA can predict complications after human leukocyte antigen (HLA)-identical SCT when CTLp and HTLp frequencies are analyzed in PBMC of the respective stem cell graft [bone marrow (BMMC) or granulocyte colony-stimulating factor (G-CSF)-mobilized PBMC] and compared to PBMC of PB. Host-specific CTLp frequencies measured in 25 patients and HTLp frequencies analyzed in 6 patients were low in all responder cell sources. CTLp and HTLp frequencies seen against HLA-mismatched unrelated third-party cells were high, but third-party-specific CTLp and HTLp frequencies were lower in G-CSF-PBMC than in PBMC (p=0.047 for CTLp frequencies). Host-specific CTLp frequencies analyzed in all responder cell sources did not predict acute or chronic graft-versus-host disease (GVHD). Lower CTLp frequencies were detected in all responder cell sources from patients who relapsed after SCT than in patients without relapse, but the differences between both groups were statistically significant only in PBMC. In conclusion, a significant correlation was detected only between relapse and CTLp frequencies measured in PBMC. The lower frequency of third-party-specific cells in G-CSF-PBMC indicates that the mobilization procedure with G-CSF itself may influence results.Abbreviations BMT Bone marrow transplantation - CTLp Cytotoxic T-lymphocyte precursor - G-CSF Granulocyte colony-stimulating factor - GVHD Graft-versus-host disease - HTLp Helper T-lymphocyte precursor - LDA Limiting dilution analysis - PBMC Peripheral blood mononuclear cells - PBSC Peripheral blood stem cells - SCT Stem cell transplantation     

Peripheral lymph node helper T-cell recovery after syngeneic bone marrow transplantation in mice prepared with either gamma-irradiation or busulfan

The optimum marrow ablative regimen for preparing recipients of bone marrow transplantation (BMT) has not been established. gamma- Irradiation, but not busulfan, produces a characteristic microvascular injury pattern which results in depressed capacity of normal lymphocytes to localize into the lymph nodes of syngeneic murine BMT recipients. Since peripheral lymph nodes are important sites for initiation and amplification of immune responses, the preparative regimen might delay recovery of regionally compartmentalized immune functions after BMT. We evaluated the effects of busulfan and gamma- irradiation on the phenotypic and functional reconstitution of helper T- cell function within the peripheral lymph nodes of BMT recipients. Both marrow ablative regimens caused a protracted delay in regeneration of peripheral lymph node CD4+ T cells. Specific helper T-cell functions, such as contact hypersensitivity and alloantigen responses, remained significantly depressed in the lymph nodes of irradiated mice for prolonged periods (up to 60 weeks). These responses recovered more rapidly in busulfan-treated BMT recipients. In contrast, the capacity of peripheral lymph node T cells to provide "help" for antigen-specific immunoglobulin production was only transiently depressed by either preparative regimen. Our experiments confirm the hypothesis that the marrow ablative regimen, particularly gamma-irradiation, may contribute to the period of immunodeficiency which follows BMT. The pattern of immune recovery observed suggests that preparative total body irradiation (TBI) may selectively depress the regional recovery of the TH1 [interleukin-2 (IL-2) and gamma-interferon (gamma-IFN) secreting] lymphocyte subset.     

The predictive value of helper T lymphocyte precursor frequencies for graft-versus-host disease and graft-versus-leukaemia effects in allogeneic bone marrow transplantation.

Helper T lymphocyte precursor (HTLp) frequencies determined by limiting dilution analysis were studied in the graft-versus-host direction to assess the predictive value for outcome in allogeneic BMT. The HTLp frequencies correlated with the degree of HLA disparity. HTLp frequencies from 28 HLA-identical sibling BMT pairs had a median of 1:557 362 (range 1:9511 to <1:2 500 000). The HTLp frequencies from 20 HLA-matched unrelated and partially HLA-matched related BMT pairs had a median of 1:88 110 (range 1:4139-1:736 123). The HLA-identical sibling BMT pairs were split evenly into high and low HTLp frequency groups above and below 1:500 000. There was a trend towards a higher risk for acute GVHD > or =grade II (P = 0.075) in the high frequency group. There was no difference in TRM. The high HTLp frequency group had a significantly higher risk for chronic GVHD (P = 0.04), a significantly lower risk for relapse (P = 0.01), as well as a significantly better overall survival (P = 0.045) and leukaemia-free survival (P = 0.008). The HLA-matched unrelated and partially HLA-matched related BMT pairs were split evenly into high and low HTLp frequency groups above and below 1:90 000. There was a significantly higher risk for acute GVHD > or = grade II (P = 0.007) in the high HTLp frequency group. There was a trend towards a higher TRM in the high HTLp frequency group (P = 0.05). There were no differences in chronic GVHD, risk of relapse, overall survival and leukaemia-free survival. Analyzing all 48 patients the risk of acute GVHD > or = grade II and TRM was significantly higher (P = 0.012 and 0.021, respectively) with HTLp frequencies >1:100 000 and there was a trend towards a higher risk of relapse (P = 0.058) with low HTLp frequencies <1:400 000. Patients in the intermediate HTLp frequency group 1:100 000-1:400 000 had a trend towards improved survival (P = 0.059). The HTLp frequency seems to detect clinically significant differences in alloreactivity, that can be useful in donor selection and graft engineering.     

Standardization of T-cell depletion in HLA matched bone marrow transplantation

The IBM 2991 Blood Cell Processor has been used to isolate a mononuclear cell (MNC) fraction from the marrow of 31 allogeneic donors. The MNC fraction was then incubated with a combination of two murine monoclonal antibodies MBG6 (CD6) and RFT8 (CD8) followed by two rounds of treatment with rabbit complement resulting in a marrow inoculum significantly reduced in the number of T-lymphocytes. We report here new specifications for the use of Ficoll-Metrizoate, the method used to calculate T-lymphocyte depletion and the details of our attempts to improve T-depletion. Following marrow transplantation with this T-depleted fraction, 29 patients are evaluable for engraftment, one patient failed to engraft and one died too early for evaluation. Twenty-two had no acute graft-versus-host disease (aGvHD), at a minimum of 60 d, six had grade I acute GvHD and one grade III. No correlation was found between the absolute number of MNC infused and time to engraftment, nor any relationship between the number of residual viable T-lymphocytes in the infused marrow and the incidence of GvHD, but the patient with the most severe aGvHD also had the highest number of T-lymphocytes infused.     

T-cell depleted bone marrow transplantation for plasma cell myeloma

Summary A 37-year-old male patient with advanced refractory plasma cell myeloma underwent T-cell depleted bone marrow transplantation (BMT) after 7 years of active disease previously treated with combination chemotherapy and irradiation. After the BMT there was marked clinical improvement and the patient is currently in good clinical condition two years after the BMT was performed. However, residual myeloma cells are still seen in the marrow and stable levels of paraprotein are still present in the serum. No GVHD was encountered after BMT. The problems of BMT in myeloma are discussed with a review of the current pertinent literature.     

Early host CD8 T-cell recovery and sensitized anti-donor interleukin-2-producing and cytotoxic T-cell responses associated with marrow graft rejection following nonmyeloablative allogeneic bone marrow transplantation

OBJECTIVE: We developed a nonmyeloablative conditioning regimen for allogeneic bone marrow transplantation (BMT) followed by donor lymphocyte infusions (DLI) for treatment of chemotherapy refractory malignancies. Although the majority of patients who receive this regimen achieve lasting mixed or full allogeneic chimerism, approximately 30% show initial mixed chimerism followed by loss of the donor graft. These patients recover host hematopoiesis without significant cytopenias. To assess the role of immunologic rejection in graft loss, we compared T-cell recovery and in vitro alloresponses in six patients who lost their marrow graft to that in 16 concurrent patients with sustained donor chimerism. PATIENTS AND METHODS: Conditioning included pretransplant cyclophosphamide (150-200 mg/kg), thymic irradiation (700 cGy), and pre- and post-transplant equine antithymocyte globulin (ATG; ATGAM). HLA-identical related donor BMT was followed by DLI at approximately day 35 in patients without graft-vs-host disease. RESULTS: The group with transient chimerism showed significantly increased circulating host T-cell (median 416 cells/mm(3) vs 10 cells/mm(3), p<0.05) and CD8 T-cell numbers (354 cells/mm(3) vs 71 cells/mm(3), p<0.05) compared to the group with stable mixed or full donor chimerism within the first 100 days post-BMT. All DLI recipients who lost chimerism following DLI had greater than 80% recipient T cells at the time of DLI, whereas those with persistent chimerism had <60% host T cells. Graft rejection was associated with the development of a sensitized anti-donor bulk cytotoxic T-lymphocyte (CTL) response in 4 of 6 evaluated patients, compared to only 1 of 10 evaluated patients with sustained chimerism (p<0.05). Additionally, 3 of 5 evaluated transient chimeras showed high anti-donor CTL precursor frequencies in limiting dilution assays, and 3 of 4 evaluated transient chimeras showed high anti-donor interleukin-2 (IL-2)-producing T-helper (T(H)) cell frequencies. High anti-donor T(H) or cytotoxic T-lymphocyte precursors were not detected in sustained chimeras. CONCLUSION: These data indicate that loss of chimerism in patients receiving this nonmyeloablative regimen is due to immune-mediated rejection. This rejection appears to bemediated by recovering recipient cytolytic CD8(+) cells as well as IL-2-producing recipient T(H) cells. These data are the first to demonstrate sensitization of recipient anti-donor IL-2-producing cells in association with human marrow allograft rejection.     

Interleukin 2 enhances cytotoxic cell function in vitro after T-cell depleted marrow transplantation

After T-cell depleted marrow transplantation, there is a rapid recovery of cytotoxic effector cells, with activity against targets not susceptible to killing by 'resting' natural killer cells. These targets include Epstein-Barr virus transformed B cells and leukaemic cell lines. Activated killer cell function declines by 3 months after transplantation. We find that when CD3 negative effector cells are obtained from these patients and cultured in vitro with interleukin 2 there is a further enhancement of cytotoxic activity against a range of target cells in the early post-transplant period, and a restoration of high level cytotoxic activity to effector cells obtained 3 months or more after the procedure. These results may have relevance to attempts to reduce the incidence of leukaemic relapse, and EBV + ve lymphoma outgrowth after T-cell depleted BMT.     

Extended-cycle elutriation to adjust T-cell content in HLA-disparate bone marrow transplantation

We report the development of a double-cycle elutriation (DCE) technique separating 3 or greater logs of T cells from a stem-cell-enriched marrow fraction and the results of phase I T-cell depletion studies with HLA-disparate related bone marrow transplantation (BMT) donors in two patient groups. In group 1, 10 patients with refractory hematopoietic malignancies received combination chemotherapy, total body irradiation (TBI), and immunosuppression (pre- and post-BMT), and hematopoietic rescue with a marrow transplant, depleted of T cells by elutriation. Potentially to promote engraftment and a graft-versus- leukemia (GVL) effect, 0.5 to 0.75 x 10(5) T cells/kg were added back. All 10 patients engrafted. Five patients developed acute graft-versus- host disease (GVHD; four grade II, one grade III) and two subsequently developed chronic GVHD. Two patients have relapsed (median follow-up, 206 days; range, 46 to 1,035). Four patients died of BMT-related complications (three of infection, one of veno-occlusive disease [VOD]). Four patient are disease-free survivors (median follow-up, 960 days; range, 670 to 1,035). Group 2 included five infants, four with congenital lymphohematopoietic deficiencies and one with refractory acute lymphocytic leukemia (ALL). In these infants, busulfan and increased cyclophosphamide were substituted for TBI. Only the ALL patient received added T cells. Three patients engrafted: one has stable mixed chimerism, one relapsed with ALL, and one rejected the marrow. One patient had primary autologous recovery, while another failed to engraft. None developed GVHD. We conclude that, in this setting of HLA-disparate BMT with post-BMT antithymocyte globulin (ATG) and corticosteroids, DCE significantly depletes T cells from the marrow and that a defined number of T cells can be added without the occurrence of severe GVHD.     

Adult T-cell leukemia successfully treated with allogeneic bone marrow transplantation

Adult T-cell leukemia (ATL) is associated with human T-cell leukemia virus type 1 (HTLV-1) and is known to be a refractory disease of highly poor prognosis. We describe a case of ATL treated with allogeneic bone marrow transplantation (allo-BMT). The allo-BMT successfully induced complete remission in the patient. Currently, at 24 months post BMT, there has been no evidence of minimal residual disease (MRD) detected by polymerase chain reaction (PCR) assay for the T-cell receptor gamma chain gene. By contrast, PCR analysis demonstrated the reappearance of the cells harboring the integrations of the HTLV-1 proviral DNA 9 months after the BMT. These findings may imply a reversion to the carrier state rather than the recurrence of the leukemia from the MRD. The clinical consequence of our case illustrates that allo-BMT is an effective therapy, at least for achieving longer disease-free survival in ATL.     

Lymphokine production by T-cell clones after human bone marrow transplantation

T cells recovering after bone marrow transplantation (BMT) were analyzed for their phenotypic and functional features by two-color immunofluorescence and a high efficiency cloning technique. A predominance of cells co-expressing natural killer (NK)-related surface antigens, such as Leu 7 (CD57) and CD11b, was detected within both the CD4+ and CD8+ subsets from 5 months postgrafting onward. Such cells are virtually absent among normal circulating CD4+ cells and account for a minority (approximately 30%) of normal CD8+ cells. Postgrafting T cells representative of the whole range of NK-related antigen co-expression were selected from six patients for clonal analyses. In control subjects, 63% and 41% of the CD4+ and CD8+ clones, respectively, produced interleukin-2 (IL-2) whereas approximately 30% of either CD4+ or CD8+ control clones produced interferon (IFN)-gamma. At variance, and irrespective of their CD4+/CD8+ phenotype, lower proportions of BMT recipient-derived clones produced IL-2 (20% and 12%, respectively), whereas the majority of both CD4+ and CD8+ clones (75% and 71%, respectively) released high amounts of IFN-gamma. Purified populations of CD57+/CD11b+ v negative cells from two BMT recipients and two control subjects were cloned and subsequently evaluated for IL-2 and IFN-gamma production. CD57+/CD11b+ cell-derived clones were poor IL-2 producers in both normal subjects and BMT patients. In contrast, IL-2-producing clones were frequent (62% to 79%) among those derived from CD57-/CD11b- cells from normal subjects, whereas they were still represented at lower than normal proportions, ie, 25% to 41%, among clones generated from BMT recipients. CD57+/CD11b+ cells gave rise to comparably high proportions of IFN-gamma producing clones in both normal subjects and BMT recipients (approximately 80%). In contrast, IFN-gamma producing clones were approximately 25% to 50% of CD57-/CD11b- cell-derived clones in both normal subjects and BMT patients. Therefore, while the predominance of NK-related antigen-positive T cells may be predictive of poor IL-2 and high IFN-gamma production, the immune derangement in long-term BMT recipients is further enhanced by the finding that all T cells may be poor IL-2 producers. It is also suggested that IL-2 production is a preferential function of T cells that do not express CD57 and CD11b, whereas IFN-gamma production is attributable to T cells that express CD57 and CD11b.     

Studies on the mechanism of tolerance or graft-versus-host disease in allogeneic bone marrow recipients at the level of cytotoxic T-cell precursor frequencies.

Previous studies demonstrated that the frequency of donor-versus-host-reactive cytotoxic T-cell precursors (CTL-p) before allogeneic bone marrow transplantation (BMT) from matched unrelated donors correlates with the incidence of graft-versus-host disease (GvH-D). We investigated whether clinical manifestations of GvH-D after HLA-identical sibling BMT are accompanied by an increased frequency of minor histocompatibility antigen (HA)-specific CTL-p. We further asked whether changes of third-party-reactive CTL-p as a measure of overall immunocompetence are related to infectious complications frequently seen immediately after BMT. Eighteen patients (16 with an HLA-identical bone marrow graft, two with either one HLA-A or one HLA-DR mismatch) were studied. Limiting dilution analysis (LDA) was used to assess donor CTL-p frequencies against recipient pre-BMT, donor, and third-party targets in a follow-up study. Eight cases receiving HLA-identical marrow grafts never developed signs of GvH-D. Undetectable or very low frequencies (1/131,458) of minor HA-specific CTL-p were demonstrated pre-BMT. Two recipients, one of an HLA-A- and one of an HLA-DR-mismatched graft, exhibited low frequencies of recipient-specific CTL-p (1/66,920 and 1/85,577, respectively) before transplantation, which further decreased despite mild GvH-D grade I, or decreased within 3 months after grafting in the other case. Eight patients receiving HLA-identical grafts developed GvH-D. Recipient-specific CTL-p were less than 1/300,000 in five patients during limited GvH-D (four with grade I and one with grade II disease of the skin), but were detectable in three patients presenting with extensive GvH-D grades II to III and ranged from 1/7,993 to 1/210,108. The differences in post-BMT recipient-specific CTL-p frequencies between patients with GvH-D grades 0 to I (median, less than 1/300,000) and those with GvH-D grades II to III (median, 1/111,970) were statistically significant (P less than .05). Posttransplant lymphocytes from all 18 patients contained less than 1/300,000 CTL-p with specificity for donor targets. Comparison of third-party-reactive CTL-p frequencies between donor and post-BMT recipient lymphocytes showed a severe and long-lasting depletion subsequent to BMT, which was not related to infectious complications. Again, these differences reached the level of statistical significance (median CTL-p before BMT, 1/4,417; after BMT, 1/14,289; P less than .005).(ABSTRACT TRUNCATED AT 400 WORDS)     

Infectious complications after allogeneic bone marrow transplantation with and without T-cell depletion of donor marrow

Summary The infectious complications during different time intervals after allogeneic bone marrow transplantation (BMT) (day 0 to day 30, 31 to 100, 101 to 365, 366 to 730) were reviewed in 67 adult patients, 27 of whom received transplants without T-cell depletion (TCD) using methotrexate or cyclosporin A for prophylaxis of graft-versus-host disease (GvHD) and 40 of whom received donor marrow with TCD using the monoclonal anti-lymphocyte antibody campath-1 and human complement. The use of TCD reduced the incidence and severity of GvHD significantly (p<0.01), but was associated with an increased rate of graft rejections. During all time intervals patients with TCD had a similar, lower or statistically significantly lower number of bacterial, fungal or viral infections and a statistically significantly lower number of lethal infections (p=0.05) as compared with patients without TCD. This finding might be explained by the fact that with TCD immunological reconstitution can take place unimpaired by GvHD or its prophylaxis or treatment, resulting in a decreased incidence of infections.

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Infektiöse Komplikationen nach allogener Knochenmarktransplantation mit und ohne T-Zell-Depletion des Spendermarkes

Zusammenfassung Bei 67 erwachsenen Patienten wurden die Infektkomplikationen nach allogener Knochenmarktransplantation (KMT) während verschiedener Zeitintervalle (Tag 0 bis Tag 30, 31 bis 100, 101 bis 365, 366 bis 730) untersucht. Siebenundzwanzig Patienten erhielten ein Transplantat ohne T-Zell-Depletion (TCD) unter Verwendung von Methotrexat oder Cyclosporin A als Prophylaxe einer Graftversus-Host-Reaktion (GvHD) und 40 Patienten ein Transplantat mit TCD durch Einsatz des monoklonalen Lymphozyten-Antikörpers Campath-1 und humanem Komplement. Die TCD verminderte Häufigkeit und Schweregrad der GvHD signifikant (p<0.01), war aber mit einer erhöhten Transplantatabstoßung verknüpft. Während der verschiedenen Zeitintervalle hatten Patienten mit TCD eine ähnliche, niedrigere oder statistisch signifikant niedrigere Anzahl von bakteriellen, mykotischen oder viralen Infektionen und außerdem eine statistisch signifikant niedrigere Anzahl von tödlichen Infektionen (p=0.05) im Vergleich zu Patienten ohne TCD.

     

Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation

Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-gamma, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.     

Recovery of immurioglobulin isotypes following T-cell depleted allogeneic bone marrow transplantation

After conventional bone marrow transplantation serum IgG, IgM and IgA levels fall from pre-transplant levels and may not return to normal for 3-12 months. In contrast IgE may rise to supranormal levels, an event that may be associated with graft-versus-host disease. We have investigated the recovery of immunoglobulin isotypes in the recipients of allogeneic marrows depleted of T-cells to prevent graft-versus-host disease. We find that pre-transplant IgG, IgM and IgA levels are maintained throughout the post-transplant period but that there is a short-lived rise in IgE about 3 weeks after transplantation: this rise occurs in the absence of clinically detectable graft-versus-host disease. We conclude that specific T-cell depletion does not impair and may actually enhance the functional recovery of B cells after allogeneic BMT.     

Haemolysis after T-cell depleted bone marrow transplantation involving minor ABO incompatibility

9 recipients of T-cell depleted allogeneic bone marrows (8 group A, 1 group AB) from group 0 donors were monitored after transplantation. Free anti-A/B was demonstrable in 8 of the 9 recipients 10–19 d post-transplant, 5 patients developed a positive direct anti-globulin test and 7 showed a rise in bilirubin. The presence of antibody was generally unrelated to the infusion of incompatible plasma, although 2 patients who also received anti-CMV immunoglobulin subsequently shown to contain high titre IgG anti-A/B were more severely affected, sustaining a fall in Hb of up to 2 g/d. These observations suggest that, after T-cell depleted bone marrow transplantation, immunocompetent B lymphocytes of donor origin are transferred, secrete antibody in the recipient, and may be responsible for self-limiting haemolytic episodes.     

多种免疫抑制剂联合应用于单倍体骨髓移植

目的：观察多种免疫抑制剂联合使用后半相合未去T细胞骨髓移植术后患者免疫功能的恢复情况。方法：38例白血病患者接受HLA2～3个位点不匹配的亲缘骨髓移植，用ATG、CD25抗体、CSA、MTX、MMF预防移植物抗宿主病(GVHD)，定期对受者在移植术后1、3、6、12、18个月的外周血淋巴细胞亚群和血清免疫球蛋白进行检测。结果：移植术后1个月患者淋巴细胞各亚群均明显下降，CD4^ T最明显，CD4^ T细胞绝对数在 6月达200个／μ，导致CD4／CD8持续倒置，在移植后18个月才逐渐恢复。CD3^ 、CD8^ 、CD19^ B细胞计数在BMT后的6～12个月基本恢复。因常规输注丙种球蛋白BMT后IgG一直正常，IgM和IgA分别在移植后6～9个月和18个月恢复。结论：单倍体相合骨髓移植后1年患者免疫功能处于低下状态，CD4^ T和IgA恢复最慢，CD4^ 细胞百分比和绝对值持续的低下，CD4／CD8持续倒置是移植后感染高发的原因，该期间要适当应用免疫支持治疗及环境保护。     

Natural killer cell activity following T-cell depleted allogeneic bone marrow transplantation

We have examined the recovery of natural killer (NK) cell function in seven recipients of MHC matched T cell depleted bone marrow allografts. NK cell activity against the erythroblastoid line K562 recovers 2-3 weeks after transplantation. Recipients also show a high level of killing of the T cell target HSB2 and of EBV transformed lymphoblastoid cell lines (B-LCL). This activity peaks at 4-6 weeks and declines towards normal by 12-14 weeks after transplantation. Although killing of HSB2 and B-LCL is usually the property of activated NK cells, few of these patients had any obvious 'trigger' of such activation: none had CMV infection, there were no episodes of graft rejection, and only two patients had mild and transient grade I graft versus host disease (GvHD). We conclude that T cell depletion does not affect the reconstitution of NK cell function and that NK cell activation occurs after T depleted bone marrow transplantation even in the absence of clinically detectable GvHD, graft rejection or CMV infection.