Immune Reconstitution after Allogeneic Stem Cell Transplantation - a Systematic Single Center Survey

The renewal of the immune system after allogeneic hematopoietic stem cell transplantation (HSCT) is a complex process not fully understood. Recently, the use of reduced intensity conditioning (RIC) regimens, new anti-viral drugs and intensified GvHD treatment changed the landscape of allogeneic transplantation. Here, the influence of several parameters on the development of the cellular and humoral immunity of 136 patients consecutively transplanted in a single center was analyzed.

All adult patients transplanted during a period of three years (September 2010 to August 2013), were analyzed in respect of immunoglobulin levels with the turbidimetric method, serum electrophoresis, immunofixation and lymphocyte subset counts by flow cytometry. Also the occurrence of a monoclonal/biclonal gammopathy was reported. In addition, we looked for donor chimerism, B and T cell receptor repertoire of peripheral blood samples. Most patients received a reduced conditioning regimen; nearly all patients received either anti-thymoglobulin (ATG) or alemtuzumab (25/136 matched related donors) leading to a relatively low rate of chronic GvHD (40%). The immune parameters obtained one year after stem cell transplantation were correlated with relevant factors of stem cell transplantation, namely the conditioning regimen, diagnosis, relapse rate, age, sex and history of CMV infection, acute and chronic GvHD using Pearson correlation, t-test and regression analysis (SPSS).

A normal CD4/CD8 ratio at day 360 after HSCT was only seen in 14% of evaluable patients, while it was reduced in 83%. This was mainly due by an impaired CD4 cell count while the CD8 cell count was even increased in 42%. The CD8 cell count was significantly higher in patients after CMV infection (p<0.001) and in those not receiving alemtuzumab as part of the conditioning regimen (p=0.003). The IgG level was normal in 51%, reduced in 31% and increased in 17 % of tested patients. The IgG level correlated with a history of CMV infection, NK, CD4, and CD8 cell count (all p≤0.025); but age, sex, diagnosis, relapse, use of RIC, acute and chronic GvHD had no significant impact. The development of a new clonal gammopathy was found in 18 patients after undergoing a HSCT and was in nearly all cases reversible. Interestingly, this was associated with chronic GvHD (p=0.034), but not any of the other parameters.

Almost all patients show a compromised immune system one year after allogeneic stem cell transplantation mainly characterized by an inverted CD4/CD8 ratio. Whether an increased CD8 cell count may not only reflect the response to viral infections but in some cases improved immunosurveillance, is hard to document. Interestingly, the immunoglobulin levels are highly variable ranging from antibody deficiency to hypergammaglobulinemia positively correlating with CMV reactivation. Continuous disbalanced immunoreactivity indicated by clonal gammopathy was associated with chronic GvHD. The systematic evaluation of these basic immune parameters may lead to better therapeutic guidance in patients after allogeneic HSCT.