Course Of Bone Marrow Transplantation Research Articles

Immunological Senescence and Thymic Function in Transplantation

In the field of organ transplantation, the state of thymic function has not been a major concern but data from bone marrow transplantation studies have unravel the persistence of some thymopoiesis in the adult and, more importantly, the possibility of reinducing it. Given the central role of the thymus in tolerance, these facts have stimulated the interest in the biology of the thymus in humans. Contemporarily, basic research has provided new tools, if imperfect, to monitor thymic function, that is, T-cell receptor excision circles, markers for lymphocytes recently emigrated from the thymus and new imaging techniques. The deployment of these new tools is already changing some paradigms and has now established that re-enactment of thymic activity in the course of bone marrow transplantation or in patients with human immunodeficiency virus on highly active anti-retroviral therapy is beneficial and that can be achieved in the adult. Clinical trials using thymopoiesis-stimulating factors are underway. On the other hand, the discovery that the thymus contains a broad representation of self-antigens and that this depends on the expression of the product of the gene AIRE by the medullary thymic epithelial cells opens the possibility of manipulating central tolerance. Current protocols inducing microchimerism to generate tolerance to solid organ grafts suggest that this could be a feasible therapeutic goal. Therefore, there are many signs indicating that a period of translational research applying the principles of thymic biology and central tolerance to transplantation has already started.

Psychosocial Predictors of Distress in Parents of Children Undergoing Stem Cell or Bone Marrow Transplantation

To examine psychosocial predictors of distress (mood disturbance, perceived stress, caregiver burden) in parents of children undergoing stem cell or bone marrow transplantation (BMT). Measures of prior illness experiences, premorbid child behavior problems, family environment, social support, and parental coping behavior were obtained from the resident parents of 151 children prior to the children's admission for BMT. Parents subsequently completed assessments of their mood disturbance, perceived stress, and caregiving burden on a weekly basis through week +6 post-BMT, and then monthly through month +6 post-BMT. Significant changes were observed in parental distress across the course of BMT. After correcting for demographic and medical factors, several significant predictors of parental distress trajectories were identified, including prior parent and patient illness-related distress, premorbid child internalizing behavior problems, the family relationship dimensions of the family environment, and parental avoidant coping behaviors. Multivariable models were developed using a hierarchical modeling approach. The best-fit model accounted for approximately 50% of the variance in parental global distress. Subgroups of parents at higher risk for increased distress during the acute phase of transplant have been identified. These findings can help target parents who may be in greater need of intervention aimed at reducing transplant-related distress.

Non-myeloablative stem cell transplantation for induction of host-versus-graft tolerance for adoptive immunotherapy of malignant and nonmalignant diseases and towards transplantation of organ allografts

ENGRAFTMENT of donor stem cells in the course of bone marrow transplantation (BMT) results in consistent host-versus-graft (HVG) transplantation tolerance. Although BMT is an important clinical tool for treatment of patients with a wide variety of malignant and life-threatening non-malignant diseases, it cannot yet be considered as a practical tool for routine induction of tolerance to organ allografts. This is due to the fact that BMT, even between fully matched siblings, is still hazardous, expensive, and associated with high rates of procedurerelated morbidity and mortality. As will be discussed in this article, based on recent innovations in clinical transplantation of stem cells, we have reason to believe that safer and less costly BMT procedures may become available in the near future. Our optimism stems from the fact that successful and safe engraftment of donor BMT can be accomplished with non-myeloablative conditioning induced with minimal conditioning based on immunoregulation rather than myeloablation.

Effects of imatinib on bone marrow engraftment in syngeneic mice.

Chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias arise from the genetic reciprocal translocation t(9;22), forming the BCR-ABL fusion gene. These lead to the expression of the constitutively active tyrosine kinase BCR-ABL, which is the causative oncogene for these leukemias. Allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) is currently considered the only curative treatment for chronic myeloid leukemia (CML). Recently, the selective tyrosine kinase inhibitor imatinib mesylate (Glivec, formerly STI-571) has been shown to induce durable hematologic and major cytogenetic responses in a high percentage of patients with chronic phase CML. In patients with advanced disease remissions are transient and most patients relapse despite continued imatinib treatment. Some of these patients go on to receive allogeneic BMT or SCT, during which administration of imatinib is usually discontinued as it is believed to interfere with bone marrow engraftment. In this study, we examined the effect of imatinib on hematopoietic engraftment in a syngeneic mouse model. We found that imatinib has no significant influence on hematopoietic recovery in lethally irradiated mice in vivo. Thus, our results suggest that continued administration of imatinib in the course of BMT or SCT may be a feasible therapeutic regimen.

Hemostatic Abnormalities Following Bone Marrow Transplantation

Hemostatic abnormalities in 26 patients following bone marrow transplantation (BMT) were examined. In the event-free survival group, the plasma levels of antithrombin (AT) and protein C (PC) were significantly decreased 1 and 2 weeks after BMT, and the plasma levels of thrombomodulin (TM) and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-I complex) were significantly increased from 4 weeks to 13 weeks after BMT. Excepting AT, there was no significant difference in hemostatic parameters before BMT among the event-free survival, 6-month survival, and death within 6 months groups. On day 0 following BMT, only plasma AT levels were significantly lower in the 6-month survival group than in the death within 6 months group. From 1 to 3 weeks after BMT, plasma levels of AT or PC were significantly lower in the death within 6 months group than in the 6-month survival group. From 1 to 5 weeks after BMT, the plasma levels of TM and tissue type plasminogen activator-plasminogen activator inhibitor-I complex (tPA-PAI-I complex) were significantly higher in the 6-month survival group than in the death within 6 months group. From 1 to 13 weeks after BMT, the plasma levels of D-dimer or soluble fibrin monomer (SFM) were significantly higher in the death within 6 months group than in the 6-month survival group. There was no remarkable difference in plasma levels of thrombin-antithrombin comlex or plasmin-plasmin inhibitor complex following BMT between these groups of patients. These findings suggest that the decrease in the plasma AT or PC level reflects early occurrence of complications of prognostic significance and that the increase in vascular endothelial cell markers such as plasma levels of TM or tPA-PAI-I complex reflects occurrence of complications during the middle course of BMT. Plasma levels of D-dimer and SFM may be useful markers for predicting complications associated with poor prognosis after BMT.

Speechless after Bone Marrow Transplantation: A Rare Complication of Parainfluenza Virus Related Group in an Adult

Upper respiratory tract (URT) viral infections may cause severe consequences during myeloablative bone marrow transplantation (BMT). We present a patient with parainfluenza virus (PIV) infection during the course of BMT. He remained relatively asymptomatic during the course of cytopenia, but presented with complete loss of voice and severe laryngitis a few days after engraftment, which is not usual for adult PIV infections. Seroconversion to PIV and marked increase in antibody titres was demonstrated, with complete lymphoid engraftment. Our case illustrated that the virulence of some URT viral infections depend on host immune factors, and may remain latent until graft versus host responses can be mounted.

Effects of cyclosporin A on hepatitis C virus infection in bone marrow transplant patients

The hepatitis C virus (HCV) infection has, in general, been considered not to affect liver function severely during the course of bone marrow transplantation (BMT) except for late hepatitis which coincided with a decrease in immunosuppressive therapy. We examined serial sera of two patients with positive HCV antibody who underwent allogeneic BMT and found that while the dose of cyclosporin A tapered off, the serum concentration of HCV core protein increased before the occurrence of hepatitis. This suggests that viral reactivation and growth might be one of the important mechanisms of hepatitis after BMT in patients with positive HCV antibody.

Recombinant cytokines and hematopoietic growth factors in allogeneic and autologous bone marrow transplantation.

Use of recombinant hematopoietic growth factors in the course of bone marrow transplantation has revolutionized this modality by significantly improving the safety of the procedure. It is anticipated that use of cytokines in combination and the introduction of newer agents will further reduce costs and improve antitumor responses as well.

Serum levels of interleukin 6, interleukin 8, and C-reactive protein after human allogeneic bone marrow transplantation.

Serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) were measured every second day from day -6 to day +86 in 24 patients undergoing allogeneic (n = 23) and syngeneic (n = 1) bone marrow transplantation (BMT). Endogenous serum levels of IL-6, IL-8, and CRP were further analyzed during complications after BMT, such as fever of unknown origin (FUO), severe infectious complications and acute graft-versus-host disease (GVHD). In addition, CRP levels were measured in 10 patients with interstitial pneumonitis of various origins (CMV, idiopathic). In all 24 patients IL-6 and CRP levels showed a characteristic monophasic pattern. After a slight decrease in the first days after BMT, a significant increase was observed, starting on day +3/+5 (P < 0.05) and reaching peak levels on day +9/+11 (P < 0.01). CRP had a similar pattern, with an increase in serum levels on day +3/+5 and maximum levels one to three days after the IL-6 peak was reached. The magnitude of the peak was related to the development of complications in the further course of BMT and was high in patients with and low in patients without complications. Serum levels of both molecules returned to baseline after day 14 posttransplant. Increased IL-6 and CRP levels were observed in the further course of BMT during severe infections or FUO either on the day of clinical onset (IL-6) or three days later (CRP), but not during acute GVHD grade III/IV. CMV interstitial pneumonitis (CMV-IP) was accompanied by an increase in CRP levels, while no such elevations were observed in patients with idiopathic interstitial pneumonitis (IIP). Elevated IL-8 serum levels occurred during bacterial infections, but to a lesser amount also during GVHD and CMV-IP. In conclusion, a characteristic pattern of IL-6 and CRP was observed after allogeneic BMT and a further increase associated with infectious complications. Since no significant elevations were seen in patients with GVHD, we conclude that both molecules are not involved in the induction of GVHD and might be useful diagnostic tools for the prediction and diagnosis of infectious complications after BMT. In contrast, assessment of IL-8 serum values does not permit clinical complications to be specified.

Biological and clinical aspects of hematopoietic stem cells.

Recent advances in cell isolation techniques have greatly enhanced our understanding of the phenotype and function of hematopoietic stem cells in mice and humans. Many clinical studies have established the efficacy of using peripheral blood stem cells to supplement or replace bone marrow transplantation as a therapeutic modality for several types of malignancies. This new approach to malignant disease management, perhaps in combination with posttransplantation cytokine therapy, promises to completely alter the clinical course of bone marrow transplantation.

Observations on the effects of hematopoietic colony-stimulating factors on the clinical course of bone marrow transplantation.

The use of the hematopoietic colony-stimulating factors (CSF) in clinical oncology and infectious disease has profound implications for the practice of medicine. The ability to influence the hematopoietic system with these factors offers the potential to reduce the morbidity and mortality associated with the use of chemotherapy, particularly intensive chemotherapy, and also to influence the outcome of various nonmalignant disorders of hematopoiesis.KeywordsHematopoietic ProgenitorIntensive ChemotherapyAutologous Bone Marrow TransplantationHematopoietic RecoveryBone Marrow SupportThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Serum thymidine kinase, a possible marker for monitoring the effect of bone marrow transplant treatment in early recovery phase.

We measured serum thymidine kinase (TK) activity with a radioenzyme assay system employing [I-125]-iododeoxyuridine as the tracer on serial specimens from five bone marrow transplant (BMT) patients before and after transplantation. The serum level of TK activity in the 4 patients with effective BMT treatment ranged from 3.0 to 16.9 U/L (mean, 7.80 U/L) before transplantation and from 27.3 to 236.1 U/L (mean, 82.95 U/L) after the BMT treatment. Mean serum TK activity increased 13.17-fold (range, 1.68 to 29.14-fold). In contrast, the activity in the patient with ineffective BMT treatment was not significantly different during, before, or after BMT treatment. In addition, serum TK activity in BMT patients was well correlated with the change in the number of leukocytes before and after BMT treatment [r = +0.709 (p less than 0.01), y = 0.012 x +0.87]. We conclude that the determination of serum TK activity in BMT patients is very useful in monitoring the course of bone marrow transplantation in the early recovery phase.

The diagnosis and treatment of idiopathic edema on the C-L service

s from C-L Forum The Diagnosis and Treatment of Idiopathic Edema on the C-L Service Kathleen France, Marijo Tamburrino, Nancy Campbell, ]udy Pent-z, Cynthia Evans, Medical College of Ohio, Toledo, OH Idiopathic edema is a pathological state of fluid retention lacking evidence for cardiac, renal, hepatic, or allergic disease. It is more often identified in females of reproductive age. Some authors have associated the onset with psychic stress or psychotropic medications. Both patients who abuse diuretics, thereby producing secondary hyperaldosteronism, and the idiopathic edematous patient describe complicated and confusing symptoms. Psychiatric consultants may be requested to evaluate these patients and assist in their management. The reestablishment of normal dopaminergic activity reduces symptoms when diuretics are of no avail. A case will be presented to demonstrate current theoretical understanding of the disorder and treatment approaches. Psychological and Immunological Reactions of Family Members to Patients Undergoing Bone Marrow Transplantation Ann D. Futterman, David K. Wellisch, Jacob Zighelboim, Herbert Weiner UCLA School of Medicine, Departments of Psychiatry and Medicine, Los Angeles, CA Both patients and family members must endure a great deal of psychological distress during bone marrow transplantation (BMT) procedures. To date, 16 family members (either spouses or parents) of patients undergoing BMT procedures at UCLA have been evaluated immunologically and psychologically over the course of BMT. Blood is drawn and psychological questionnaires are obtained from family members immediately prior to the patient’s BMT, when the patient enters protective isolation, when the patient leaves isolation or has Do Not Resuscitate (DNR) status enacted, and when the patient leaves the hospital. Although results are preliminary, there appear to be significant and progressive declines in natural killer cell activity, response to anti-T3 cells, CD8 suppressoricytotoxic T cell numbers, and lymphocytosis in many of the family members over the course of the transplant. Many subjects experience a decline in optimism and positive affect and an increase in negative affect over the course of the transplant. Subjects appear to receive the majority of their support from nursing staff and others on the BMT service, and family members. Notable immunological changes have been identified in some subjects immediately after stressful events occurred during the transplant. Effects of Stress on Tumor Metastasis and Response to Cyclophosphamide T. Giraldi, L. Perissin, S. Zorzet, V. Rapozzi, M.G. Rodani lstituto di Biologia, Facolta di Medicina, Universita di Udine 33100-Udine, Italy A relatively large number of reports exist in the literature showing that stress can influence the incidence and progression of tumors in laboratory animals, but little attention has been given to the problem of metastasis formation. The aim of the present work has thus been to determine the effects of applying defined paradigms of psychological stress to mice kept in a low-stress environment on primary tumor growth and spontaneous metastasis of Lewis lung carcinoma. The stressors examined are the anticipatory anxiety caused by the periodic application of spatial disorientation (SD), early maternal deprivation, behavioral despair, physical restraint, and avoidable versus unavoidable footshock in conditioned animals. SD reproducibly causes a significant and marked increase in metastasis weight independent from primary tumor, whose magnitude varies with a circannual rhythm; marginal and scarcely reproducible results have been obtained with the other experimental paradigms used. The nature of the mediators operative in the effects of SD have been examined by direct hormonal assay, and by treatment of the animals with pharmacological inhibitors or antagonists of specific neuroendocrine effecters. In these conditions, the participation of plasmatic glucocorticoids appears to be insignificant, that of P-endorphin and prolactin are significant, whereas the adrenergic system appears principally involved. An increase in the urinary excretion of melatonin is observed upon application of SD, which accompanies the observed increase in lung metastasis weight. The antitumor resistance factors of the host modulated by SD appear to participate in determining the action of the antitumor drug cyclophosphamide (CY), as its curative effects are abolished in mice subjected to SD. The effects

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Dermatologists are not so familiar with transplantation immunity, especially graft-versus-host disease (GVHD). In order to understand GVHD, GVHD and other related diseases are discussed. The clinical course of bone marrow transplantation and GVHD are explained. GVHD is classified into congenital, iatrogenic or unknown GVHD with its origin. GVHD is also classified into hyperacute, acute or chronic GVHD with the time of onset. Pseudo GVHD (GVHD-like disease) appears following autologous transplant or syngeneic bone marrow transplantation. Postoperative erythema and post-transfusion GVHD are GVHD-related diseases and are also described.