Bone Marrow Transplantation
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December (2) 2001, Volume 28, Number 12, Pages 1175-1176
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'Altered immunity syndrome', a distinct entity in long-term bone marrow transplantation survivors?
M Trendelenburg1, M Gregor2, J Passweg2, A Tichelli2, A Tyndall3 and A Gratwohl2

1Division of Medicine, Medical Clinic B, University Hospital Basel, Basel, Switzerland

2Division of Hematology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland

3Division of Rheumatology, University Hospital Basel, Basel, Switzerland

Chronic graft-versus-host disease (cGVHD) is one of the major chronic complications of hematopoietic stem cell transplantation (HSCT) and occurs within the first years after transplantation. The close similarities between cGVHD and autoimmune diseases, such as systemic sclerosis or Sjögren's syndrome, were recognized early.1 However, follow-up data of cGVHD in long-term transplanted patients are scarce and pathogenetic mechanisms are still poorly understood. These mechanisms have gained renewed interest at a time when HSCT is discussed as a therapeutic option for severe autoimmune disorders.2 In addition, the occurrence of a syndrome smiliar to connective tissue diseases in long-term survivors which might not be related to cGVHD has been postulated.3 There are several reports on various autoantibodies being detected after HSCT.3,4,5,6 The occurrence of these autoantibodies is independent of acute or chronic GVHD and their clinical significance is unknown.

In a retrospective study, we analyzed 38 patients, all long-term survivors of at least 10 years after HSCT from an HLA-identical sibling. Data were collected during annual routine follow-up of the patients. We screened for the occurrence of autoantibodies and a possible association with symptoms of a connective tissue disease.

The following autoantibodies were analyzed by standard assays: anti-nuclear, anti-mitochondrial, anti-parietal cell, anti-heart muscle, anti-smooth muscle, anti-skeletal muscle and anti-parotid antibodies. We specifically looked for symptoms which could be related to an underlying autoimmune disease: arthralgia/myalgia, sicca syndrome (dry eyes, dry mouth), skin efflorescences, reduced exercise tolerance (Karnofsky index <100%) and fatigue syndrome. Symptoms were added in a score from 0 to 5.

Statistical analyses were carried out by the Wilcoxon Mann-Whitney U test, Fisher's exact test and Spearman rank correlation coefficient.

Of the 38 patients analyzed (19 male, 19 female), 17 had acute myeloblastic leukemia, 10 chronic myeloblastic leukemia, five severe aplastic anemia, three acute lymphoblastic leukemia, two myelodysplastic syndrome and one non-Hodgkin's lymphoma.

Autoantibodies were found in 20 patients (group I), whereas 18 patients were repeatedly negative (group II). In group I, 17 patients had anti-nuclear, two had anti-mitochondrial, three anti-parietal and three anti-heart muscle antibodies. Both groups were statistically not different concerning age (group I: median 39.5 years, range 16-59 vs group II: median 39 years, range 21-56), sex, underlying disease, time after HSCT (14.1 vs 13.7 years), sex of the donor, T cell depletion of the graft, HLA antigens, seropositivity (IgG) for CMV (8/20 vs 7/18) or hepatitis C. However, all patients with severe aplastic anemia (n = 5) were autoantibody positive.

The incidence and degree of cGVHD were not significantly different (12/20 vs 7/18), but the number of patients with ongoing immunosuppression for persistent cGVHD (5/20 vs 0/18; P < 0.05) was significant. The degree of a preceding cGVHD did not correlate with the level and/or number of the detected autoantibodies. The frequencies of restrictive pulmonary disease (3/20 vs 3/18) or elevated serum creatinine (2/20 vs 0/18) were the same in both groups. It is noteworthy that five autoantibody positive patients never had any signs of acute and/or chronic GVHD.

Autoantibody positive patients had significantly more symptoms than patients without autoantibodies (2.7 vs 1.44, P < 0.01). This difference remained significant when the five patients with ongoing immunosuppression for persistent cGVHD were excluded from the analysis (2.67 vs 1.44, P < 0.025). All scored symptoms were more frequently observed in autoantibody positive patients. The occurrence of sicca syndrome (16/20 vs 9/18; P < 0.05) and fatigue syndrome (7/20 vs 1/18; P < 0.05) was significantly more frequent. The percentage of autoantibody positive patients increased with the number of symptoms (Figure 1).

It is possible that all signs and symptoms in these patients are the consequence of subclinical cGVHD. However, there are some arguments that a novel approach is needed to understand these phenomena. The majority of the autoantibody positive patients described here did not suffer from symptoms corresponding to classical cGVHD. The degree of a preceding cGVHD correlated neither with the level and/or number of detected autoantibodies nor with the scored symptoms presented at the time point of this analysis. There were several autoantibody positive patients who had never had acute or chronic GVHD.

Furthermore, in a large study on long-term transplanted patients, 36% had a Karnofsky index <100% but only a few of them had active cGVHD.7 This fits with earlier reports that the occurrence of autoantibodies after HSCT does not correlate with cGVHD but might be rather the expression of an abnormal B cell and/or T cell reconstitution.3,4,5,8,9,10

Therefore, we hypothesize that long-term survivors after allogeneic HSCT are at risk for a skewed immune reconstitution with altered immune response leading to late secondary 'auto'-immune like phenomena. More detailed and longer analyses are needed to confirm our observation.


1 Lawley TJ, Peck GL, Moutsopoulos HM et al. Scleroderma, Sjögren-like syndrome, and chronic graft-versus-host disease. Ann Intern Med 1977; 87: 707-709, MEDLINE

2 Tyndall A, Gratwohl A. Immune ablation and stem-cell therapy in autoimmune disease: Clinical experience. Arthritis Res 2000; 2: 276-280, MEDLINE

3 Rouquette-Gally AM, Boyeldieu D, Prost AC, Gluckman E. Autoimmunity after allogeneic bone marrow transplantation. A study of 53 long-term-surviving patients. Transplantation 1988; 46: 238-240, MEDLINE

4 Chan EY, Lawton JW, Lie AK, Lau CS. Autoantibody formation after allogeneic bone marrow transplantation: correlation with the reconstitution of CD5+ B cells and occurrence of graft-versus-host disease. Pathology 1997; 29: 184-188, MEDLINE

5 Hebart H, Einsele H, Klein R et al. CMV infection after allogeneic bone marrow transplantation is associated with the occurrence of various autoantibodies and monoclonal gammopathies. Br J Haematol 1996; 95: 138-144, MEDLINE

6 Quaranta S, Shulman H, Ahmed A et al. Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation. Clin Immunol 1999; 91: 106-116, Article MEDLINE

7 Socié G, Stone JV, Wingard JR et al. Long-term survival and late deaths after allogeneic bone marrow transplantation. New Engl J Med 1999; 341: 14-21, MEDLINE

8 Vavassori M, Maccario A, Comoli P et al. Restricted TCR repertoire and long-term persistence of donor-derived antigen-experienced CD4+ T cells in allogeneic bone marrow transplantation recipents. J Immunol 1996; 157: 5739-5747, MEDLINE

9 Roux E, Helg C, Chapuis B et al. T-cell repertoire complexity after allogeneic bone marrow transplantation. Hum Immunol 1996; 48: 135-138, MEDLINE

10 Leroy E, Calvo CF, Divine MF et al. Persistence of T8+/HNK-1+ suppressor lymphocytes in the blood of long-term surviving patients after allogeneic bone marrow transplantation. J Immunol 1986; 137: 2180-2189, MEDLINE


Figure 1 The percentage of autoantibody positive patients increased with the number of scored symptoms (arthralgia/myalgia, sicca syndrome, skin efflorescences, reduced exercise tolerance (Karnofsky index <100%) and fatigue syndrome).

Received 9 May 2001; accepted 2 September 2001
December (2) 2001, Volume 28, Number 12, Pages 1175-1176
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