Circulating thymic hormone activity in patients with primary and secondary immunodeficiency diseases

Levels of circulating thymic hormone, facteur thymique serique (FTS), were quantitated in the serum of normal subjects ranging in age from three days to 85 years and in a wide variety of patients with primary and secondary immunodeficiency diseases. FTS levels were low in the serum of a high proportion of patients with common variable immunodeficiency and selective absence or deficiency of IgA. Patients with DiGeorge syndrome always had low levels. In infants with severe combined immunodeficiency (SCID) FTS levels were low in 21 of 23 instances and normal in only two. In patients classified as having primary T-cell deficiency FTS levels were regularly lower than normal as in those with osteopetrosis and ataxia telangiectasia. In patients with Wiskott-Aldrich syndrome and chronic mucocutaneous candidiasis FTS levels were frequently lower than normal. In patients with systemic lupus erythematosus (SLE) FTS levels were below the normal range in the majority of instances, whereas FTS levels within the normal range were characteristic of patients with the X-linked infantile form of agammaglobulinemia (Bruton's disease) and patients with progeria. Serums from seven patients were shown to inhibit FTS activity. Of these, serum from six patients with common variable immunodeficiency was studied for its capacity to inhibit synthetic FTS and FTS activity in normal serum. In two of these, FTS activity was inhibited in normal serum, and in five synthetic FTS activity was inhibited. Another patient with immunodeficiency, who had increased IgM levels and neutropenia, also had a serum inhibitor that was active against FTS. Search for an inhibitor of FTS in the serum of individual patients with SCID, chronic mucocutaneous candidiasis and a thymectomized infant revealed no such inhibition. Twenty-seven patients with common variable immunodeficiency were studied for both FTS activity and lymphocytic proliferative responses to phytomitogens and antigens. In 10 of these patients, FTS levels were low and in three of these 10 the responses to both mitogens and antigens were deficient; in four, responses were normal for both, and in three, the responses to antigen were low but the responses to mitogen were normal. In four of 27 patients with low FTS titers, however, an inhibitor against FTS activity was present in their serum, but their proliferative response to mitogens was normal and in two responses to antigens were reduced as well. This finding may explain the frequent dissociation of FTS activity and lymphocyte functions.     

Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) is the most common cause of poor long-term outcomes after allogeneic bone marrow transplantation (BMT), but the pathophysiology of chronic GVHD still remains poorly understood. We tested the hypothesis that the impaired thymic negative selection of the recipients will permit the emergence of pathogenic T cells that cause chronic GVHD. Lethally irradiated C3H/HeN (H-2k) recipients were reconstituted with T-cell-depleted bone marrow cells from major histocompatibility complex [MHC] class II-deficient (H2-Ab1-/-) B6 (H-2b) mice. These mice developed diseases that showed all of the clinical and histopathological features of human chronic GVHD. Thymectomy prevented chronic GVHD, thus confirming the causal association of the thymus. CD4+ T cells isolated from chronic GVHD mice were primarily donor reactive, and adoptive transfer of CD4+ T cells generated in these mice caused chronic GVHD in C3H/HeN mice in the presence of B6-derived antigen-presenting cells. Our results demonstrate for the first time that T cells that escape from negative thymic selection could cause chronic GVHD after allogeneic BMT. These results also suggest that self-reactivity of donor T cells plays a role in this chronic GVHD, and improvement in the thymic function may have a potential to decrease chronic GVHD.     

Use of thymic grafts or thymic factors to augment immunologic recovery after bone marrow transplantation: brief report with 2 to 12 years' follow-up

Thymus tissue implants, thymic epithelial cells obtained from third party donors sharing one HLA-A and -B locus with the recipient, or the thymic hormones thymosin fraction 5 and thymopentin were given to recipients of HLA-identical sibling bone marrow to prevent chronic graft-versus-host disease (GVHD) and accelerate immunologic reconstitution. The clinical courses of 17 patients receiving thymus tissue and 18 patients receiving thymic hormones were reported initially 5 years ago and showed no difference in the incidence of chronic GVHD or immunologic recovery from those of concurrent or historical controls. We report here for the first time nine new patients who received thymus tissue implants with modifications of the culture method to lower the number of lymphocytes in the transplanted tissue with the intent of reducing rejection of the thymus tissue grafts. The clinical outcomes and immunologic functions of these nine patients were similar to those of the recipients of the earlier thymus tissue implants. With follow-up now ranging from 2.2 to 12.3 years (median 6.7) for the total group, 16 patients are alive. Seven never developed chronic GVHD. Nine were treated for chronic GVHD, seven of whom recovered and are leading normal lives, one has chronic pulmonary insufficiency, and one is disabled from chronic GVHD. We conclude that thymus tissue grafts or thymic epithelial cells partially HLA-matched to the recipient, thymosin fraction 5, or thymopentin used as described were not effective in reducing the incidence of chronic GVHD, improving immunologic recovery, or altering long-term survival.     

Thymic dysfunction in childhood T-acute lymphoblastic leukemia: a possible linkage with a primary thymus involvement.

Experimental models, clinical and histopathological observations suggest a thymic origin of childhood T acute lymphoblastic leukemia (T-ALL). We studied thymic epithelial function in childhood T-ALL as compared to normal controls in order to improve our understanding of the cellular immunodeficiency mechanisms operating in a thymus-linked malignant process. The levels of Facteur Thymique Sérique (FTS) were measured in 9 patients at diagnosis, according to the rosette inhibition assay of Dardenne & Bach (1975). This method is based on the capacity of human serum containing FTS activity to confer on rosette-forming cells (RFC) from adult thymectomized mice a sensitivity to azathioprine identical to that of normal mouse RFC. All patients presented low age-corrected titres of FTS. No zinc deficiency was found, suggesting that low FTS levels are not related to unexpressed FTS biological activity. Plasma from all the children studied contained factors capable of inhibiting the biological activity of FTS in vitro. However, the nature of this inhibitor has not yet been elucidated. Our study shows the presence of a thymic dysfunction in childhood T-ALL, which could partially explain the immunodeficiency described in these patients. The linkage of the leukemic process with a primitive thymic involvement is discussed.     

Detection of circulating endogenous interleukin-3 in extensive chronic graft-versus-host disease.

Recent data suggest that activated immune cells and their products are involved in the initiation and progression of graft-versus-host disease (GVHD). To test whether the production of endogenous interleukin-3 (IL-3), a product of activated immune cells, might be an indicator of disease activity in GVHD, we analysed sera of 61 bone marrow transplant (BMT) recipients for IL-3 levels by using an enzyme linked immunosorbent assay. Measurable levels (greater than 25 pg/ml) of endogenous IL-3 were detected in a significant subgroup (5/16 patients, 31.25%) of allograft recipients suffering from extensive chronic GVHD, but not in patients with limited chronic GVHD (n = 6) or in those without signs of chronic GVHD (n = 17). In IL-3 positive patients, IL-3 levels were not associated with pathologic conditions (such as infectious disease) other than GVHD. IL-3 levels were undetectable in disease-free phases preceding severe chronic GVHD. Lower levels of IL-3 were measured in chronic GVHD patients during extensive disease while on high dose steroid medication compared with before and/or after (p less than 0.02). IL-3 was also detected in a small group (2/17) of patients suffering from acute GVHD. IL-3 could neither be detected in syngeneic (n = 3) nor autologous (n = 7) BMT recipients nor in the vast majority (99/100) of healthy controls. Together, measurable amounts of IL-3 are produced in a significant subgroup of patients suffering from extensive chronic GVHD.     

Pulmonary function after allogeneic hematopoietic stem cell transplantation

This study was undertaken to identify the factors influencing pulmonary function in patients who underwent hematopoietic stem cell transplantation (HCT). Pulmonary function tests were evaluated before and after HCT in 51 adult patients who underwent HCT between 1993 and 1998. The patients with hematologic malignancies were given total body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A and short-term methotrexate. Six patients suffered from acute GVHD above grade II and 27 patients suffered from chronic GVHD. The post-transplant % diffusing capacity (%DLco) 100 days after HCT was significantly lower than pretransplant values (82 +/- 21% versus 71 +/- 15%, p < 0.01). The %DLco at 100 days was significantly lower in patients with chronic GVHD than in patients without chronic GVHD (66 +/- 16% versus 77 +/- 9%, p < 0.05). These findings suggested chronic GVHD is related to the decreased %DLco values observed 100 days after HCT.     

Inhibition of prostaglandin E2 restores defective lymphocyte proliferation and cell-mediated lympholysis in recipients after allogeneic marrow grafting

Prostaglandins are said to influence T and B cell function by inhibiting the generation of interleukin 2 (IL 2) and the formation of suppressor lymphocytes. After bone marrow transplantation, patients usually have a profound immunodeficiency that persists in recipients with chronic graft-v-host disease (GVHD) and generally resolves in long- term survivors without GVHD. In vitro tests of lymphocyte function such as allogeneic mixed lymphocyte culture (MLC) and cell-mediated lympholysis (CML) have been shown to be impaired in many patients. We postulated that prostaglandin E2 (PGE2) plays a role in the impaired in vitro tests. To test this hypothesis, we studied in vitro tests in the presence of PGE2 antagonists, indomethacin, and anti-PGE2 antiserum with cells from 22 short-term patients (less than 100 days postgrafting) and 32 long-term survivors with or without GVHD. Results show that blockade of PGE2 release by indomethacin and anti-PGE2 significantly (P less than .01) enhanced the MLC (+67%) and the CML responses (+10.5%) of cells from long-term survivors with chronic GVHD but not from those of long-term, stable recipients. No enhancement of MLC and CML activity was observed with cells from donors of long-term recipients. In patients shortly after marrow grafting, enhancement in the MLC was not significant. However, CML activity in this patient group was significantly increased (+12.5% in recipients with no GVHD, 8.5% in those with acute GVHD, P less than .01). Indomethacin also suppressed the activity of nonspecific suppressor cells in patients with chronic GVHD. When cells from patients with chronic GVHD were treated with recombinant IL 2 and IL 2 combined with indomethacin, it was possible to get an additional augmentation of lymphocyte proliferation after the addition of indomethacin to IL 2-treated cultures. Thus it is very likely that PGE2 inhibits T lymphocyte proliferation, not exclusively by inhibition of IL2 production or activity. We conclude that PGE2, among other factors, may play a role in the pathogenesis of the immunodeficiency after transplantation. PGE2 does not act primarily by interfering with IL2 but presumably by inducing a suppressorlike activity.     

The pathophysiology of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) still remains the most significant complication after allogeneic hematopoietic stem cell transplantation. The disease usually appears after day 100 and is characterized by signs and symptoms similar to autoimmune diseases. The pathophysiology of chronic GVHD is poorly understood because of the lack of highly satisfactory animal models and basic studies in patients. It has not been clearly determined whether the disease is a distinct entity or a continuation of acute GVHD. In experimental and clinical studies of chronic GVHD, thymic atrophy, lymphocyte depletion, and autoantibody formation have been described. Conditioning regimens and acute GVHD may disrupt thymic function and dysregulate the negative selection process of potentially autoreactive T-lymphocytes. Disruption of thymic apoptosis and failure to eliminate the majority of self-reactive lymphocytes may lead to impairment of lymphocyte homeostasis and self tolerance. Expansion and effector functions of autoreactive T-cells will then promote autoreactive B-cell activation and production of autoantibodies with target-organ damage. Chronic GVHD requires continuous CD4+ T-cell help for B-cells and is known as T-helper 2 (Th2) disease. Murine models have demonstrated the roles of interleukin (IL)-12 and IL-18 in chronic GVHD. IL-12 may cause an increase in donor CD8+ cytotoxic T-cells leading to conversion of chronic GVHD to an acute form. In contrast, IL-18 prevents chronic GVHD by decreasing numbers of CD4+ (Th2) cells and host-reactive B-cell activation and reducing alloantigen-specific immune response. Mouse and human cellular genomics coupled with advances in cell biology in donor-recipient tolerance will improve our understanding of transplantation immunology and may offer new approaches to the challenge of ameliorating chronic GVHD.     

DNA synthesis in human blood mononuclear cells correlates with severity of acute graft-versus-host disease

'Spontaneous' blood mononuclear cell DNA synthesis was studied in 83 bone marrow transplantation (BMT) recipients and 58 controls. Prior to BMT, patients with chronic myeloid leukemia had increased DNA synthesis, which decreased dramatically after conditioning and transplantation. After engraftment, patients with syngeneic marrow or allogeneic marrow without graft-versus-host disease (GVHD) had increased DNA synthesis compared to healthy controls. However, patients with acute GVHD (AGVHD) had a significantly increased DNA synthesis compared to patients without GVHD (p less than 0.001). DNA synthesis increased with increasing grade of AGVHD. Among patients with severe AGVHD, recipients of HLA-mismatched marrow had higher lymphocyte DNA synthesis at diagnosis of GVHD and maximum values compared to HLA-matched siblings (p less than 0.05). At diagnosis of GVHD, patients who developed grades II-IV GVHD with progressive disease had higher DNA synthesis, 23.9 +/- 4.0 x 10(3) c.p.m. (mean +/- SE) compared to 11.1 +/- 2.7 x 10(3) c.p.m. in patients in whom GVHD resolved (p less than 0.02). DNA synthesis during GVHD was lower in sheep erythrocyte rosette-forming cells (E-RFC) compared to enriched non-E-RFC. Herpes simplex virus, cytomegalovirus, bacterial septicemia and chronic GVHD had no major effect on lymphocyte DNA synthesis in these patients.     

Plasma zinc level and thymic hormone activity in young cancer patients

It has been reported that in many neoplastic diseases, including leukemia, alterations in plasma zinc levels may frequently occur, although the causes for such alterations have yet to be clearly defined. Since zinc is required to induce biological activity to thymulin (Zn-FTS), a biochemical defined thymic hormone, and marginal zinc deficiencies may prevent its peripheral biological activation, we investigated the plasma level of zinc and of both active thymulin (Zn- FTS) and total zinc saturable thymulin (Zn-FTS + FTS) in 91 young patients affected by acute lymphoblastic leukemia (ALL) at various stages of the disease. It was discovered that the plasma zinc level was reduced at the onset and relapse, whereas in complete remission and in off-therapy it was in the normal range. Total zinc-saturable thymulin concentration did not change during the disease, whereas the active fraction was reduced at the onset and in relapse when compared with values observed in the other stages of the disease or in healthy controls. These data suggest that zinc plasma deficiency is present in ALL patients at the onset and during relapse, and that such a deficiency causes a decrease in the activity of thymulin despite a nearly normal production by the thymus. An impairment of peripheral immune efficiency in ALL patients is commonly found. The existence of positive correlations between zinc or active thymulin and peripheral immunological parameters (phytohemagglutinin [PHA] and concanavalin A [ConA]) at various stages of the disease suggests a link between derangement of peripheral immune function, thymic hormone activity, and zinc failure. These findings, considered together, suggest the possibility of a carefully controlled clinic trial with zinc in ALL patients at the onset and in relapse even in the light of in vitro ineffectiveness of physiological zinc or thymulin concentrations on the duplicative index of human lymphoblastoid cells.     

Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program

Chronic graft-versus-host disease (GVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. We retrospectively analysed 2937 patients who underwent bone marrow transplantation from an unrelated donor (UR-BMT) facilitated by the Japan Marrow Donor Program (JMDP) and survived beyond day 100 after transplantation. The cumulative incidence of chronic GVHD (limited + extensive) or extensive chronic GVHD at 5 years post-transplant was 45.8% and 28.2%, respectively. On multivariate analysis, seven variables predicting chronic GVHD were identified: recipient age over 20 years, donor age over 30 years, primary diagnosis of chronic myeloid leukaemia, human leucocyte antigen (HLA)-A or -B mismatch, total body irradiation-containing regimen, platelet count not having reached 50 x 10(9)/l by day 100, and prior acute GVHD. Among 2609 patients with haematological malignancy, overall survival was significantly higher in patients with limited chronic GVHD but lower in patients with extensive chronic GVHD compared with those without chronic GVHD. The cumulative incidence of relapse among patients with limited or extensive chronic GVHD was significantly lower than that among patients without chronic GVHD. Our results suggest that limited chronic GVHD provides a survival benefit to patients with haematological malignancies by reducing the risk of relapse without increasing the risk of death from chronic GVHD.     

Markedly increased serum erythropoietin levels following conditioning for allogeneic bone marrow transplantation

Serum erythropoietin (EPO) levels were measured by radioimmunoassay in 36 patients undergoing allogeneic bone marrow transplantation (BMT). Serum EPO levels before conditioning treatment for BMT were generally higher than the levels obtained from healthy controls (49 +/- 17 (SEM) and 17 +/- 0.6, respectively). One day prior to BMT, after conditioning by chemotherapy with or without total body irradiation, the mean EPO level was markedly elevated (218 +/- 23 U/l, p less than 0.001) and reached to its highest level at 1 week post-BMT (269 +/- 40 U/l). Although, the EPO levels were significantly lower at 1 month (98 +/- 24 U/l, p less than 0.001), they were still elevated up to 3 months post-BMT, after which they gradually normalized. Patients given methotrexate and cyclosporine for prophylaxis against graft-versus-host disease (GVHD) had significantly lower EPO levels during the first 3 months post-BMT than patients transplanted with T cell-depleted marrow (p less than 0.05). Patients with post-transplant nephrotoxicity had lower, though not statistically significant, EPO levels than patients with normal renal function (p = 0.07). Acute GVHD and number of blood transfusions had no influence on serum EPO levels after BMT.     

Inhibition of calcineurin phosphatase activity in adult bone marrow transplant patients treated with cyclosporine A

In vitro studies have demonstrated that cyclosporine A (CsA) acts by inhibiting the phosphatase activity of calcineurin, an important mediator of T-cell activation. The relationship of CsA administration in vivo, calcineurin activity, and graft-versus-host disease (GVHD) has yet to be studied. The calcineurin activities of mononuclear cells isolated from 62 bone marrow transplant recipients and 12 normal volunteers were determined and analyzed with respect to administration of CsA, presence or absence of CsA in plasma, and presence or absence of GVHD. Of 62 patients, 33 were taking CsA and 29 were not. Early posttransplant (< 100 days), the calcineurin activity of patients on CsA was significantly lower than that of patients not on CsA (P = .0004) and than that of normal volunteers (P < .0001). Similarly, late posttransplant (> 100 days), the calcineurin activity of patients taking CsA was inhibited compared with normal volunteers (P < .05). The calcineurin activity of patients with acute GVHD who were taking CsA was lower than that of patients on CsA without acute GVHD matched for time posttransplant (P = .02). Calcineurin activity in patients on CsA with chronic GVHD was similar to those without chronic GVHD on drug. In conclusion, calcineurin activity is significantly suppressed by in vivo administration of CsA. The lower calcineurin activity of patients on CsA with acute GVHD suggests that CsA-resistant GVHD is not the result of inadequate suppression of calcineurin activity. These data suggest that if inhibition of calcineurin is the only physiologic target of CsA administration, simply increasing doses of CsA or treatment with other inhibitors of calcineurin, such as FK506, would not be expected to ameliorate GVHD.     

Survival after bone marrow transplantation from cytomegalovirus seropositive sibling donors

HLA-A2-restricted T cells show peptide-specific activity against cytomegalovirus and leukaemia cells. We retrospectively analysed the influence of donor cytomegalovirus serostatus on the outcome of 103 consecutive patients who had leukaemia and who received bone-marrow transplants from HLA-identical sibling donors. We found that donor cytomegalovirus seropositivity significantly improved overall survival (p=0.02) as a result of lower relapse incidence (p=0.035) in HLA-A2-positive but not HLA-A2-negative recipients. In HLA-A2-positive recipients donor cytomegalovirus seropositivity was associated with chronic graft-versus-host disease (GVHD), but even in patients without chronic GVHD donor cytomegalovirus seropositivity significantly improved survival (p=0.0483). These preliminary data provide evidence that at least in HLA-A2-positive recipients, transplantation of bone marrow from cytomegalovirus positive, HLA-identical sibling donors seems to be associated with substantial graft-versus-leukaemia activity, and suggests a cross-reactivity of cytomegalovirus-specific donor-derived cytotoxic T cells with HLA-A2-restricted recipient minor histocompatibility antigens.     

Serum IgE levels after bone marrow transplantation

Total serum IgE levels were followed in 135 bone marrow transplant recipients in order to determine the clinical significance of post-transplant serum IgE monitoring. Patients with IgE levels less than 60 U/ml at the time of bone marrow transplantation (BMT) (59%) experienced at least one IgE peak. Patients with pretransplant IgE levels greater than or equal to 60 U/ml (16%) showed decreasing values following BMT. In 19% of patients, IgE levels were low and did not change up to 3 months after BMT. Increase in IgE levels coincided in time with engraftment (p less than 0.01) and acute graft-versus-host disease (GVHD) (p less than 0.01). Early IgE peaks were also seen in patients without GVHD. Maximal IgE values did not differ during grades II-IV GVHD compared with grades 0-1, but two or more peaks were more common in patients with grades II-IV (p less than 0.001). IgE peaks also appeared in patients receiving T cell-depleted marrow without GVHD. Syngeneic bone marrow recipients had high IgE levels after BMT. Two patients had increasing IgE values following reconditioning and retransplantation, but booster grafts had no effect on IgE levels. IgE levels were not changed during septicemia, herpes simplex virus or cytomegalovirus infections, and chronic GVHD. No linear correlation was found between serum IgE levels and CD4+/CD8+ ratios, percentages, or absolute numbers of either group of cells. It was concluded that serum IgE elevation is found in association with engraftment and acute GVHD, but is mainly caused by the conditioning treatment.     

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA(+) naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4(+) and CD8(+) cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.     

Clinicopathological features in patients with hepatic graft-versus-host disease

BACKGROUND/AIMS: Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone marrow transplantation and often results in a fatal outcome. However, hepatic manifestation of chronic GVHD accompanied by unresolved acute GVHD has not been clarified so far. The present study was intended to examine clinicopathological features in patients in which acute GVHD appeared to progress gradually into chronic GVHD. METHODOLOGY: We evaluated laboratory data, pathological features and response to immunosuppression in 11 patients whose diseases were diagnosed as hepatic GVHD, retrospectively. The patients were classified into 3 groups: acute GVHD group (n=3), non-progressive chronic GVHD group (n=5) and progressive chronic GVHD group (n=3), which means continuous liver dysfunction beyond day 100 post-transplant. RESULTS: Patients with progressive chronic GVHD showed higher peaks of aminotransferase and biliary tract enzyme levels than patients with acute GVHD and non-progressive chronic GVHD. Their biopsy specimens demonstrated severer changes in lobular parenchyma, portal area and small interlobular bile ducts. They also showed marked loss of bile ducts. Despite administration of prednisolone or dose escalation of cyclosporin A, their liver function tests did not return to normal within one year. CONCLUSIONS: In cases of liver dysfunction that emerges within 100 days after transplantation, liver biopsy appears to be important to confirm diagnosis. Patients with acute hepatic GVHD need strong immunosuppression to prevent progression to chronic GVHD.     

Elevated levels of soluble ICAM-1 in serum of patients with acute myeloid leukemia undergoing bone marrow transplantation

Serum soluble ICAM-1 concentrations were measured in 10 patients with or without chronic graft-vs.-host disease (GVHD) after allogeneic bone marrow transplantation. The serum soluble ICAM-1 levels in the patients with chronic GVHD were significantly higher than that in the patients without chronic GVHD. The data indicated that serum soluble ICAM-1 is a useful parameter for predicting chronic GVHD. © 1996 Wiley-Liss, Inc.     

Prognostic value of pretransplantation host thymic function in HLA-identical sibling hematopoietic stem cell transplantation

Thymic function is critical for immune reconstitution after hematopoietic stem cell transplantation (HSCT). We evaluated recipient thymic function before HSCT by quantifying T-cell receptor excision circles (TRECs) in pretransplantation peripheral blood lymphocytes from 102 patients who received HSCs from an HLA-identical sibling for malignant (n = 87) or nonmalignant diseases (n = 15). Median TREC value before transplantation was 257 TRECs per 150,000 CD3+ cells (range, 0-42,746). We assessed 172 TRECs per 150,000 CD3+ cells as the most discriminating TREC value for survival in a first cohort of patients (n = 62). This cut-off was validated in a second independent prospective group of 40 patients. In the 102 patients, a TREC value greater than or equal to 172 was associated with a better survival (P < .000 01), a decreased incidence of grade II-IV acute graft-versus-host disease (GVHD; P = .017), chronic GVHD (P = .023), and bacterial (P = .003) and cytomegalovirus (CMV) infection (P = .024). In a multivariate analysis, low pretransplantation TREC values were associated with a higher incidence of CMV infection (hazard ratio [HR] = 2.0, P = .06) and severe bacterial infections (HR = 2.8, P = .036). Finally, high TREC values (HR = 6.6, P = .002) and ABO compatibility (HR = 2.7, P = .02) were associated with a better survival. Therefore, recipient host thymic function assessment could be helpful in predicting HSCT outcome and identifying patients who require a close immunologic monitoring.