Work

Immune Reconstitution Following Reduced Intensity Conditioning With CAMPATH-1H Versus Total Lymphoid Irradiation/Anti-Thymocyte Globulin Prior To Allogeneic Stem Cell Transplantation

Year: 2010

Type: article

Abstract: Graft versus host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. In vivo quantitative T-cell depletion using CAMPATH-1H (anti-CD52) has been explored in an effort to prevent acute GVHD. Recently, a regimen of total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) has been shown to polarize T-cells towards an inhibitory phenotype potentially reducing the risk for GVHD. However, these strategies may lead to impaired post-transplant immune reconstitution, increased risk of tumor relapse and opportunistic infection. We compared the immune recovery of 20 patients undergoing reduced intensity conditioning with low dose CAMPATH and an initial cohort of 5 patients treated with TLI/ATG. Conditioning with CAMPATH resulted in a significant depletion of CD4 and CD8 T-cells in the early post-transplant period and persistence of CD4 T-cell depletion for 6 months. Following TLI/ATG, there was a persistent depletion of CD4 T-cells with no significant decrease in CD8 T-cells. CAMPATH was associated with a decrease in CD45RO+ memory T-cells in the early post-transplant period (27.2 to 5.7%, p=0.03). T-cell recovery in early post-transplant following TLI/ATG was associated with a rise in the relative percentages of naive T-cells (CD45RA+) (39 to 61.3%; p=0.04), central memory (CD45RO+CD62L+CCR7+) (CM) (12 to 32.8%; p=0.05), and a significant change in the central memory:effector memory (CD45RO+CD62L-CCR7-) (EM) ratio (0.2 to 1.0). The mean percentage of regulatory T-cells (CD4+CD25+FoxP3+) rose in the early post-transplant period following both regimens (p<0.03). Functional analyses demonstrated that the T-cell proliferative response to Phytohemagglutinin (PHA) was profoundly depressed following CAMPATH with mean SI decreasing from 34 pre-transplant to 1.4 Day 30. Treatment with TLI/ATG resulted in no significant change in response to PHA. Assessment of T-cell polarization after stimulation with PMA/ionomycin, recipient derived dendritic cells (DCs) or third party DCs demonstrated a rise of CD8+T-cells expressing IL-4 and IL-10 consistent with a suppressor phenotype. In summary, both CAMPATH and TLI/ATG result in CD4+T-cell depletion, but TLI/ATG resulted in persistence of memory cells, relative preservation of CM as compared to EM and intact response to mitogens. TLI/ATG therapy was associated with a more modest level of functional T-cell depletion characterized by Tc2 polarization.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2009.12.203