Immunosuppression is a key aspect of immunotoxicology. However, this does not necessarily mean that adverse effects related to immunosuppressive drugs, and especially unexpected or unintended immunosuppressive agents are indeed a major cause of concern as regards human health. During the past 4 decades, immunosuppression has been the most extensively investigated aspect of immunotoxicity. Indeed, in the mid 1960's, adverse events have been described shortly after the introduction of potent immunosuppressive drugs to prevent graft rejection in organ-transplanted patients. At roughly the same time, similar findings (later known as the Yusho or Yu-chen disease) were reported in Japanese and Taiwanese, respectively, following accidental exposure to immunosuppressive polybromobiphenyls (PCBs) via contaminated oil rice. Thus, even though the word immunotoxicology had not yet been coined and the corresponding area of toxicology not identified as such, early studies investigated the suppressive effects of medecines and chemicals on immune responses. Later on, immunotoxicologists came to standardize and validate assays and strategies to evaluate the immunosuppressive potential of these xenobiotics.

As impaired resistance toward microbial pathogens is a hallmark of immunosuppression, immunocompromised humans typically develop infectious complications.Unsurprisingly, humans treated with immunosuppressive drugs or exposed to immunosuppressive industrial/ environmental chemicals develop more frequent, often more severe and sometimes atypical infections.

Two major types of immunotoxic effects are described in immunocompromised host, namely infectious complications and virus-associated neoplasias.

1. Infectious complications

Immunocompromised patients typically develop more frequent infections. All types of microbial pathogens including bacteria, viruses, fungi and parasites can be involved. Although gastrointestinal, respiratory and skin infections are more common, all sites can be affected with the possible exception of the urinary tract.

Infections in immunocompromised patients tend to be more severe and often relapsing. They can also be atypical and then either due to microbes with no or limited pathogenicity in human subjects with a normal immune function ("opportunistic infections") or located at unusual sites (e.g. brain abcesses due to toxoplasma or systemic candidiasis.

2. Virus-associated neoplasias
Cancers of the skin and lips, and lymphoproliferative disorders associated with latent (dormant) viral infections are far more frequent in immunocompromised patients as clearly demonstrated from the results of epidemiological studies in transplanted patients.

Introduction

Further to the OCDE guideline 407 (repeated dose 28-day oral toxicity study in rodents) revised in 1995, the histopathological examination of the main lymphoid organs is nowadays the main stay of all implemented immunotoxicity guidelines whatever the type of product to be assessed in nonclinical studies. It is however relevant to keep in mind that the revised OECD guideline 407 adopted by the OECD Council was preceded by a long and hot debate whether histological  changes are reliable predictors of the immunotoxic potential of chemicals whatever their use and applications. It is obvious that no general consensus has been obtained among immunotoxicologists so that quite a few consider that functional changes may be seen with immunotoxicants that do not induce histological lesions of the lymphoid organs. Indeed, in my own experience, there are chemicals including medicines that can induce marked decreased in immune function without any histological changes whatsoever. This being taken into account the  strategy to be recommended for the detection and assessment of the unexpected immunosuppressive effects of medicines and other chemicals can be described as follows.

Standard toxicity endpoints

Guidelines recommend the use of results from standard toxicity studies for immunotoxicity risk assessment. This is particularly true for medicines (see ICH S8 guideline). Clinical signs suggestive of immunosuppression - but who can reasonably imagine that barrier-protected SPF rodents may develop infectious complications - are highlighted. Other changes in standard endpoints include hematology and clinical chemistry even though such changes are unlikely to be of immunotoxicological significance except for drugs whose mechanism of action is highly suspected to be involved, e.g. cytotoxics.

Histopathological examination of the main lymphoid organs

Nowadays, the histopathological examination of the thymus, spleen, bone marrow, lymph nodes and Peyer's patches is a routine component of standard repeat-dose toxicity studies with all medicines and many chemicals. The need for careful examination by trained pathologists has been rightfully highlighted even though the so-called Kuper's criteria appear to be rather unpractical as a routine procedure.

TDAR assay

Although the author of this document believes that no reliable immunotoxicity assessment is possible if no immune function assay is included, there is a wide consensus that a TDAR (T-Dependent Antibody Response) assay is the first-line assay when an immune function assay is considered to be needed, recommended or required. Historically, the PFC (Plaque-Forming Cell) assay was the first global immune function assay to be proposed, standardized, and widely validated.

Other immune function assays

If there is evidence or suspicion for the immunotoxic potential of a new drug candidate or molecular entity, based on the results of standard toxicity studies including histopathological examination, and of a TDAR assay,  other immune function assays may be considered:

Lymphocyte subset analysis

NK cell activity

Cell-mediated immunity

Phagocytosis and macrophage function