Lack of B cell precursors in marrow transplant recipients with chronic graft-versus-host disease

Storek, Jan; Witherspoon, Robert P.; Webb, D; Storb, Rainer

doi:10.1002/(sici)1096-8652(199606)52:2<82::aid-ajh3>3.0.co;2-1

Cited by 43 publications

(33 citation statements)

References 27 publications

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“…In this context, an impaired reconstitution of B cells was noted in case of extensive chronic GvHD. [41][42][43] Although previous investigations suggested poor T cell reconstitution due to thymic injury by GvHD, 44 recently published data showed no differences in T cell subset counts and TREC levels in dependence of GvHD. 45 This is in line with our observations, where we found no significant differences in T cell reconstitution with respect to incidence and extent of GvHD.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients

Heining

Spyridonidis

Bernhardt

et al. 2007

Bone Marrow Transplant

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Here we investigated the influence of parameters known before hematopoietic stem cell transplantation (HSCT) as well as the relevance of graft-versus-host disease (GvHD) and cytomegalovirus (CMV) reactivation on post transplant lymphocyte reconstitution in 148 patients treated in our institution between 1996 and 2003. Median patient age was 42 (19-68) years, HSCT followed standard high dose (n ¼ 91) or reduced-intensity conditioning regimens (n ¼ 57) with bone marrow (BM, n ¼ 67) or peripheral blood stem cells (PBSC, n ¼ 81) from related (n ¼ 71) or unrelated (n ¼ 77) donors. In the first months, we observed a partially faster reconstitution of CD3 þ 4 þ , CD3 þ 8 þ and CD4 þ 45RA þ T cells in patients following peripheral blood stem cell transplantation when compared to bone marrow transplantation. Prolonged CD3 þ 4 þ and CD4 þ 45RA þ lymphopenia was noted after unrelated donor HSCT and GvHD prophylaxis containing anti-T-lymphocyte globulin. Lymphocyte subset counts in patients older than the median age were comparable to those in patients transplanted at a younger age and not influenced by the conditioning regimen. CD3 þ 8 þ T cell reconstitution was strongly correlated with CMV reactivation, but not significantly affected by CMV serostatus before HSCT. Incidence or extent of GvHD did not significantly influence lymphocyte reconstitution. Therefore, the source of graft is the most predictive parameter in early lymphocyte reconstitution, but the differences in lymphocyte recovery completely resolved within the first year after HSCT.

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Section: Discussionmentioning

confidence: 99%

Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients

Heining

Spyridonidis

Bernhardt

et al. 2007

Bone Marrow Transplant

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“…58,93 Nevertheless, the similarity between many autoimmune diseases associated with autoantibodies and the clinical manifestations of chronic GVHD has always been intriguing. Patients with CMV infection may have anti-CD13 antibodies, which recognize normal structures in skin.…”

Section: Eliminate B Cellsmentioning

confidence: 99%

New approaches for preventing and treating chronic graft-versus-host disease

Lee

2005

Blood

127

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Despite improvements in the practice of allogeneic hematopoietic stem cell transplantation (HCT) over the last 25 years, chronic graft-versus-host disease (GVHD) remains a substantial problem with little change in the incidence, morbidity, and mortality of this complication. In fact, with increased use of peripheral blood, transplantation of older patients, and less immediate transplantation-related mortality, the prevalence of chronic GVHD may increase. One of the difficulties in combating chronic GVHD is a lack of understanding about the pathophysiology of the syndrome. IntroductionChronic graft-versus-host disease (GVHD) is the most serious and common long-term complication of allogeneic hematopoietic stem cell transplantation (HCT), occurring in 20% to 70% of people surviving more than 100 days. 1,2 Approximately half of affected people have 3 or more involved organs, and treatment typically requires immunosuppressive medications for a median of 1 to 3 years. Because of higher treatment-related (nonrelapse) mortality, chronic GVHD remains the major cause of late death despite its association with a lower relapse rate. 3,4 In addition, secondary malignancies are more common in people with chronic GVHD, particularly of commonly involved tissues such as mouth and skin, suggesting that chronic inflammation, prolonged exposure to immunosuppressive medications, or immune dysregulation facilitates the development of new cancers. 5 Finally, the functional consequences of chronic GVHD organ involvement are major determinants of the health and quality of life of survivors. 6,7 Despite the well-recognized adverse effects of chronic GVHD on the long-term success of allogeneic transplantation, its pathophysiology is poorly understood, and management strategies beyond systemic corticosteroids have not been established.While there are some lessons that can be translated from basic and clinical studies of acute GVHD, several lines of evidence suggest that chronic GVHD is not simply a continuation of acute GVHD, and that separate approaches will be required for its prevention and management. First, except for T-cell depletion and use of umbilical cord blood, the major innovations that have improved acute GVHD rates do not seem to have affected chronic GVHD incidence. Second, while there is significant overlap between the organs involved in acute and chronic GVHD, the distribution of affected organs in chronic GVHD is much broader. Fully evolved chronic GVHD is largely an inflammatory and fibrotic process, while acute GVHD is more likely to reflect apoptosis and necrosis. Although traditionally the boundary between acute and chronic GVHD has been set at 100 days after transplantation, more recent definitions hinge on different clinical manifestations rather than time of onset. Third, while acute GVHD is highly associated with subsequent chronic GVHD, approximately 25% to 35% of chronic GVHD is de novo without any preceding acute manifestations, while 20% to 30% of people who had acute GVHD do not go on to develop chronic GVH...

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“…Clinical GVHD decreases TREC counts, indicating an effect on thymic function, and it also decreases B cell counts. 28,33 These effects may also extend to subclinical GVHD. We and others have observed an increased frequency and severity of GVHD in adult compared to pediatric patients (Table 1).…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism

Savage

Bleesing

Douek

et al. 2001

Bone Marrow Transplant

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Summary:The effect of mixed chimerism on the pace of post-transplant immune reconstitution is unknown. Using flow cytometry, recall and neo-antigen vaccine responses, and T cell receptor recombination excision circle (TREC) quantification, we evaluated phenotypic and functional characteristics of T and B cells in nine patients following non-myeloablative, HLA-identical peripheral blood stem cell transplantation for chronic granulomatous disease. Engraftment of T cell, B cell, and myeloid lineages proceeded at similar paces within each patient, but engraftment kinetics segregated patients into two groups: adults, who became full donor T cell chimeras before 6 months (rapid engrafters) and children, who became full donor T cell chimeras after 6 months or not at all (slow engrafters). Quantitative B cell recovery was achieved by 6 weeks after transplantation in children, but was delayed until 1 year in adults. a lack of response to routine vaccinations and an increased incidence of opportunistic infections. [1][2][3][4] This dysfunction is a consequence of quantitative and qualitative defects in both the cellular and humoral arms of the immune system.Quantitative defects of the immune system after T celldepleted transplantation are characterized by varying periods of sub-normal lymphocyte subset counts. NK cells recover within 3 months after transplantation, followed by CD8 + T cells, and lastly by B cells and CD4 + T cells. 5-10Naive T cell recovery, which is important for the restoration of a normal T cell repertoire, is inversely proportional to age. [11][12][13][14][15][16] Correlating with naive T cell recovery is the fact that children respond more quickly than adults to vaccination with recall antigens after transplantation. 17Quantitative humoral defects after myeloablative transplantation include IgA, IgM, and IgG subclass deficiencies.18-21 In addition, reconstituted Ig concentrations do not necessarily coincide with functional humoral immunity. 22Opportunistic infections during the post-transplant period contribute significantly to the morbidity and mortality of this procedure. The incidence of opportunistic infections is proportional to the degree of T cell depletion. Use of less intensive non-myeloablative marrow conditioning regimens has reduced the conditioning-related toxicity, 23,24 but the effects on post-transplant immune recovery have not been studied in detail. Evidence of more rapid recovery of immune function following non-myeloablative allogeneic stem cell transplantation would further enhance the appeal of this approach.The patients in this study were being treated for chronic granulomatous disease (CGD) with an allogeneic, nonmyeloablative, T cell-depleted, hematopoietic stem cell transplant using an HLA-identical sibling donor. 25 This approach allowed for the unique opportunity to study immune reconstitution in the setting of mixed hematopoietic chimerism. Analysis of several quantitative and qualitative measures of immune reconstitution in this homogeneous group of patients reveals diff...

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Lack of B cell precursors in marrow transplant recipients with chronic graft-versus-host disease

Cited by 43 publications

References 27 publications

Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients

Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients

New approaches for preventing and treating chronic graft-versus-host disease

Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism

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