B. Griffith

Adjuvant bone marrow infusion in clinical organ transplant recipients

THE two most common causes of late organ allograft failure are complications associated with the long-term use of nonspecific immunosuppression and chronic rejection. Incidentally, this undesirable outcome could be prevented by timely adoption of clinically applicable strategies that would result in the induction of donor-specific tolerance (DST). We have previously advanced the hypothesis that stable existence of donor cell chimerism in organ allograft recipients may induce DST with ultimate enhancement of patient and graft survival.1,2 To test this hypothesis, we proceeded to augment chimerism in clinical organ transplant recipients by adjuvant perioperative unmodified donor bone marrow (BM) infusion.2,3 Reported herein is the outcome of this prospective trial in which 251 study (BM-augmented) and 129 contemporaneous controls have been accrued since its initiation in June 1992.

Clinical Significance of Cytomegalovirus-Specific T Helper Responses and Cytokine Production in Lung Transplant Recipients

Cytomegalovirus (CMV) disease continues to be a major problem for lung transplant recipients. In CMV-seropositive individuals, we detected two types of CMV-specific responses: a self-restricted response stimulated by soluble CMV antigen (sCMV-Ag) and a non-self-restricted response induced by CMV-infected cells (cCMV-Ag). Lung transplant recipients who develop the CMV-specific self-restricted T helper response have a low risk of recurrent CMV disease. In contrast, during CMV disease, lung transplant recipients exhibit only the non-self-restricted T helper responses. We characterized the T cell activation and the kinetics of cytokine production of sorted CD4+ and CD8+ T cells from PBLs of CMV seropositive donors. The two types of CMV antigens induced cytokine production in both T cell subsets. We also performed competitive RT-PCR for Granzyme B (GB) in BAL cells of lung transplant recipients prior to, during and following CMV disease. CMV disease was associated with increase in GB gene expression when was accompanied by acute cellular rejection while it remained low in patients with CMV disease that did not have a complicated course. In summary, CMV-activated T cells within the allograft may produce inflammatory cytokines and effector molecules that may promote allograft rejection.

Immune modulation in organ allograft recipients by single or multiple donor bone marrow infusions

The discovery of persistent alloantigen (i.e., chimerism) in the lymphoid and nonlymphoid tissues of successful long-term organ transplant recipients has prompted many to conclude that this phenomenon plays an important role in allograft acceptance.1,2 These findings have been corroborated in experimental models of transplantation (Tx) tolerance.3 Although the precise phenotype of cells involved in the induction of observed donor-specific tolerance (DST) is unclear, there exists overwhelming evidence suggesting that perhaps immature dendritic cells, which are resident within the graft and known to migrate after Tx, modulate host anti-donor effector responses.4 As these cells are of bone marrow (BM) origin, it was rational to propose that perioperative donor BM infusion may augment this phenomenon with resultant salutary effect on patient and graft survivals. In 1992 we initiated a clinical trial involving perioperative infusion of unmodified BM cells obtained from the vertebral bodies of cadaveric donors into abdominal and thoracic organ allograft recipients. An interim analysis of the outcome in these patients is reported at their most recent follow-up.

An internet-based intervention to improve mental health and medical compliance in heart transplant recipients

the liver transplant performed prior to the lung transplant (PREVLITX) and 48 with a simultaneous lung and liver transplant (SIMLITX). The indications were cystic fibrosis (CF) in 23 patients, -1-antitrypsin deficiency ( -1) in 4 cases, primary pulmonary hypertension (PPH) in 5 patients, and various other diagnoses (N 6). Diagnosis was not reported in 16 cases. In 22 patients a heart/lung-liver transplant was performed. Out of the 54 procedures registered a single lung Tx was performed in 22 cases and a bilateral in 32 cases. Survival was computed using the Kaplan-Meier method for transplants performed prior to June 30, 2000: this reduced cohort included 6 transplants in the PREVLITX group and 43 in the SIMLITX group. The overall survival for both groups was 80%, 71%, 64%, 56%, and 56%, respectively, at 1, 3, 12, 36 and 60 months. The survival of the SIMLITX group was 77%, 67%, 59%, 51%, 51% at same time points. Survival for the patients who received a lung Tx after previous liver Tx was 100% at 1 year. Insufficient follow-up was available to compute survival at later time points in this group. The diagnosis groups in this cohort were too small to compare. Albeit the number of all LuLiTx procedures that have been performed worldwide is small, in selected patients this treatment modality seems to lead to survival that is comparable to what is currently achieved following lung transplantation. This strongly suggests that the lung rather than the liver is the organ that limits the long-term survival following combined LuLiTx and it is to be expected that improvements in lung transplantation will also positively impact on the outcome following LuLiTx.

Long-term mental health burden of family caregiving to heart transplant recipients

Objective: For most heart transplant (tx) recipients, family members adopt key caregiving roles in the maintenance of the recipient’s long-term post-tx health. There is little evidence beyond the initial recovery period regarding mental health risks and benefits associated with caregiving in this context. We examined prevalence and risk factors for depressive and anxiety-related disorders in caregivers through 3 years after the recipient’s tx. Procedures: In a cohort of 205 heart recipients, 190 identified a primary family caregiver. Caregivers received psychiatric and psychosocial evaluations at 2-, 7-, and 12-mos. post-tx, with long-term reevaluation at 36-mos. post-tx. Data on recipients’ physical health and post-tx course were obtained from medical records and nurse evaluations. Survival analysis determined the cumulative rates psychiatric disorders and the role of psychosocial risk factors in the caregiver sample. Results: Caregivers’ rates of depressive and anxiety-related disorders were considerably elevated over rates among (a) tx recipients themselves, and (b) community and chronic disease populations. By 3 years post-tx, the cumulative risks were: Major Depressive Disorder, 32.9%, Adjustment Disorders, 36.0% (30.1% with anxious mood); Post-Traumatic Stress Disorder related to the tx, 24.5%, Generalized Anxiety Disorder, 8.0%, and any assessed disorder, 57.4%. In contrast to earlier analyses showing that psychiatric disorder was most likely during the first year post-tx for recipients, caregivers showing a continued increase in prevalence over the entire 3-year period. Among the factors increasing caregivers’ risk (p .05) for psychiatric disorder were: being the recipient’s spouse (rather than another relative), performing more daily caregiving tasks, greater time restriction due to caregiving, a poor relationship with the recipient, and low social supports from family and friends. Conclusions: There is a need for appropriate educational and clinical interventions to tx families, many of whom enter the tx experience with little knowledge as to what to expect in terms of daily life in the long-term post-tx.

Psychiatric and psychosocial issues and intervention among ventricular assist device patients

Candidates for heart transplantation face increasingly lengthy waits for donor hearts. In the United States, candidates may wait for well over 12 months (United Network of Organ Sharing statistics for 1994), and during this period, life-threatening deteriorations in their condition often occur. When death is imminent or when survival to transplant is unlikely given declining clinical condition, mechanical circulatory support can often be successfully utilized to bridge patients to cardiac transplantation. By mid-1992, a total of 380 persons had received one of the four most-used types of ventricular assist devices approved as bridges in the United States (38). These devices include the Pierce-Donachy Assist Device (Thoratec, Berkeley, CA) (n = 172 bridged patients by August, 1992); the Abiomed BVS-5000 (Abiomed Cardiovascular Inc., Danvers, MA) (n = 58 patients); the Novacor Left Ventricular Assist System (Novacor Division, Baxter Health Care Corporation, Oakland, CA) (n = 124 patients), and the CardioWest device (CardioWest, Inc., Tempe, AZ) (n = 26 patients). Clinical reports of patients supported by these and similar devices approved more recently show not only remarkable physical rehabilitation in many cases after device insertion, but excellent post-transplant survival rates that meet and sometimes exceed survival rates in nonbridged patients (21,38).