Effect of Highly Active Antiretroviral Therapy and Thymic Transplantation on Immunoreconstitution in HIV Infection

Abstract

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.

Association between Larger Thymic Size and Higher Thymic Output in Human Immunodeficiency Virus–Infected Patients Receiving Highly Active Antiretroviral Therapy

“…Furthermore, hematopoietic progenitor cells regain function during HAART and seed the thymus with functional T cell progenitors [16,27]. One study has reported a relationship between the increase in TREC levels during HAART and development of response to neoantigens, which further supports the suggestion that TREC levels increase as a result of de novo lymphopoiesis [29]. Furthermore, in a population of untreated HIV-infected patients, lower TREC levels have been shown to be associated with faster progression to AIDS.…”

Allogeneic intra-BM-BMT plus adult thymus transplantation from same donor has benefits for long-term survival even after sublethal irradiation or low-dose BM cell injection

“…TT alone has been clinically used for the treatment of DiGeorge syndrome and HIV infection. 17,18 From the ethical and clinical viewpoints, it would seem to be difficult to obtain the thymus and BMCs from the same young donors. However, we have recently shown that even MHC-mismatched thymus grafts can support thymopoiesis, which is comparable to a matched thymus graft.…”

“…[13][14][15][16] However, it is unknown whether BMT plus TT is effective when using a nonmyeloablative regimen and/or when transplanting insufficient numbers of BMCs. In addition, TT has only been clinically applied to patients with DiGeorge syndrome or HIV infection who show hypoplasia of the thymus; 17,18 the effects of TT on BMT have not been extensively examined.…”

Immune reconstitution strategies in HIV

“…Transduction of CD34 + hematopoietic stem cells with anti-HIV ribozymes is also being evaluated as a possible self-renewing means of protecting progeny T-cells and monocytes from further HIV infection [59]. The transplantation of fetal thymus has been proposed, but rejection of the transplanted tissue has proven to be a significant obstacle [60]. The thymus is an ongoing focus of research, and given that significant thymic activity persists, even in older HIV-infected patients, new strategies, such as the use of interleukin-7 and stem cell factor to encourage thymic proliferation [61].…”