It is widely accepted that there is a causal association between Kaposi sarcoma-associated herpesvirus (KSHV) and Kaposi sarcoma (KS). However, the majority of individuals infected with KSHV never develop KS. Here, we present a unique familial case of classic KS, in which the disease occurs in 4 siblings who have no recognized underlying immunodeficiency. We examine risk factors that could play a role in this condition, including KSHV infection, KSHV DNA load, genetic variants of KSHV, infection with additional viruses, interleukin-6-promoter polymorphism, and HLA genotype. We hypothesize that a genetic susceptibility to KS, in combination with KSHV infection, may play an important role in the presented familial case.

Natural killer (NK) cell activity, the autologous mixed lymphocyte reaction (AMLR) and proportions of T cell subpopulations (CD3+/CD4+ and CD3+/CD8+) and NK cells (CD16+) were studied in 21 patients with bilateral primary breast cancer (BBC), 10 patients with single-breast cancer (SBC) and 20 healthy controls. All patients studied had no evidence of disease and had been off radiotherapy and/or chemotherapy for at least 1 year. Ten patients with BBC were also treated with tamoxifen. Patients with SBC had NK cell activity, AMLR responses and T cell subpopulations that were comparable to those of normal controls. In patients with BBC, a significant (P < 0.01) increase in NK activity compared to that in normal controls (42 +/- 13% versus 21 +/- 10%, effector-to-target cell ratio, 25:1) and a significant (P < 0.05) decrease in CD4+ T cell proportions (30 +/- 15% versus 49 +/- 13%) and absolute numbers (472 +/- 82/mm3 versus 953 +/- 131/mm3) were found. However, the proliferative response of BBC patients' T lymphocytes in AMLR was in the range of the normal controls. Lymphocytes derived from 10 BBC patients treated with tamoxifen exhibited NK cell activity that was comparable to that of normal controls and patients with SBC, and was significantly (P < 0.01) reduced compared to the pretreatment period. BBC patients who received tamoxifen also show a reduction in the proportion of CD4+ T cells and in AMLR proliferative responses, which decreased compared to levels in normal controls. Taken together, these results indicate that long-term tamoxifen treatment modulates immune responses in BBC patients.

In an attempt to abrogate the deleterious effects of graft-versus-host disease (GVHD), allogeneic transplantation for nonmalignant diseases was performed using high-dose CD34-cell infusion, partial T cell depletion, and no posttransplantation GVHD prophylaxis. Between 1998 and 2004, 16 patients with matched related donors were treated. Median age was 1.5 years (range, 5 months-18 years). The conditioning regimen consisted of busulphan 16 mg/kg, cyclophosphamide 200 mg/kg, antithymocyte globulin (ATG) 25 mg/kg, and fludarabine 200 mg/m(2). No GVHD prophylaxis was given. High doses of CD34 cells, positively selected by immunomagnetic beads, were infused at a median dose of 10.7 x 10(6) CD34/kg (range, 7.4-50 x 10(6)). A total of 1 x 10(5)/kg T cells were given. All patients engrafted, with no graft rejections. All were alive and well at a median of 37 months posttransplantation (range, 18-89 months). Only 1 patient developed chronic GVHD. No episodes of severe infection occurred during or after transplantation. Immunologic reconstitution with CD3/CD4 T cells > 200/microL was observed at a median of 117 days and that with naive T cells (CD4/CD45RA) at a median of 188 days posttransplantation. Our findings suggest that allogeneic transplantation from a matched family donor for nonmalignant disorders can be successfully performed using high doses of CD34 cells, moderate T cell depletion, and no posttransplantation immunosuppression.

Allogeneic transplantation in non- malignant inherited diseases is primarily performed to correct the basic defect by repleting stem cells capable of producing the deficient component. T cells in such situations are needed to facilitate engraftment and immunological reconstitution but, due to the non-malignant nature of the basic defect, no graft versus tumor effect is needed. Moderate T cell depletion - 105 T cells/kg- given in the setting of matched related transplant could abrogate GVHD, without negatively affecting engraftment. Presented herein is the long- term outcome and chimeric status of 18 children following allogeneic stem cell transplantation for non-malignant disorders using moderate T cell depletion with no post transplant immune suppression. Patients and methods: 18 consecutive patients with non-malignant diseases were transplanted at the Rambam Medical Center, Haifa, Israel, for the following disorders: Six patients with thalassemia major, 3 with immunodeficiency, 3 with metabolic disorders (Hurler syndrome (2), San Felippo (1)), 2 with adreno-leuco-dystrophy (ALD), 2 with familial hemophagocytic lymphohistiocytosis (HLH), 1 with chronic granulomatous disease (CGD) and 1 with mitochondrial neuro-gastrointestinal encephalopathy (MNGIE) disease. Median age at transplantation was 22 months (range: 5 months–18 years). Peripheral blood stem cells were collected from matched related donor after priming with G-CSF. Conditioning regimen included busulphan 12–16mg/kg administrated over 4 days (days-9,-8,-7,-6), cyclophosphamide 120–200 mg/kg given over 4 days (days -5,-4,-3,-2), ATG (Fresenius) 25mg/kg given over 5 days (days-9,-8,-7,-6,-5), fludarabine 150–200mg/m2 administrated over 5 days (days -9,-8,-7,-6,-5), cyclosporine 1mg/kg only given for 9 days prior to transplantation during conditioning. T cell depletion was performed by positive selection of CD34 cells by immunomagnetic beads (CliniMACS). On day 0 high dose of CD34 cells were given, median CD34/kg- 10.5x 106 (range: 7.4–50x106). 105 T cells per kg were added. No prophylaxis for GVHD was given post transplant. Results: All patients engrafted. Neutrophil engraftment occurred at a median of 10 days (range: 8–13 d), platelet transfusion independence occurred at a median of 20 d (range:11–34 d). Two out of 18 patients (11%) developed GVHD, 1 patient with thalassemia major who developed chronic GVHD and 1 with MNGIE disease who developed acute as well as chronic GVHD. Regarding chimeric status, 3 patients developed 100% donor chimerism, 2 of them experienced GVHD. 13 patients had >50% donor chimerism while 2 had < 50% donor chimerism. The chimeric status has remained steady with a median follow-up of 61 months (range: 27–114 mon). There were no graft rejections. All patients, those with complete donor chimerism as well as those with mixed donor chimerism, are alive and well each with very significant clinical improvement and without disease deterioration over the years. Conclusion: Long term follow-up confirms the safety and efficacy of allogeneic SCT from matched family donors for patients with non malignant disorders using moderate T cell depletion and no post transplant immunosuppression. These data emphasize that in allogeneic transplantation of non-malignant disorders there is probably no need for full donor chimerism in order to achieve long term successful clinical outcome. Chimeric status, clinical outcome and GVHD with a median follow-up of >5 years. Chimeric Status no.of Pts. Diagnosis Clinical outcome-all alive GVHD 100% donor 3 CGD, Thalassemia, MNGIE disease Correction of basic defect; transfusion independence 2/3 >50% donor 13 Thalassemia (3)
 Immunodeficiency (3)
 Metabolic disease (3)
 ALD (2)
 HLH (2) Transfusion independence
 Resolved
 Major clinical response
 Major clinical response
 Resolved 0/13 <50% donor 2 Thalassemia (2) Transfusion independence 0/2